TUGAS MAKALAH SISTEM PENGHANTARAN OBAT

“SISTEM PENGHANTARAN OBAT PADA KOLOID YANG MUNCUL DENGAN

SOLID LIPID NANOPARTIKEL ( SLN )”

Dosen Pengampu : M. Fatchurrohman, M.Farm.

Disusun Oleh :

Nama : Amaliyana Mega Dharma

Nim : 175010144

UNIVERSITAS WAHID HASYIM SEMARANG

FAKULTAS FARMASI

2020
 DAFTAR ISI

DAFTAR ISI…………………………………………………………………………………i

KATA PENGANTAR……………………………………………………………………….ii

BAB I PENDAHULUAN……………………………………………………………………1

A. Latar Belakang………………………………………………………………………1

BAB II LANDASAN TEORI……………………………………………………………….2

B. Landasan Teori……………………………………………………………………...2

C . Keuntungan dan Kerugian Solid Lipid Nanopartikel……………………………3

a. Keuntungan…………………………………………………………..………….3
b. Kerugian………………………………………………………….………...……4
D. Karakteristik Solid Lipid Nanopartikel…………………………………….…….4

E. Metode Solid Lipid Nanopartikel………………………………………………….7

F. Aplikasi Solid Lipid Nanopartikel……………………………………………………..11

i
 KATA PENGANTAR

Assalamu’alaikum warahmatullahi wabarakatuh

Segala puji bagi Allah SWT yang telah memberikan saya kemudahan sehingga saya dapat
menyelesaikan makalah ini dengan tepat waktu. Tanpa pertolongan-Nya tentunya saya tidak
akan sanggup untuk menyelesaikan makalah ini dengan baik. Shalawat serta salam semoga
terlimpah curahkan kepada baginda tercinta kita yaitu Nabi Muhammad SAW yang kita nanti-
natikan syafa’atnya di akhirat nanti.

Saya mengucapkan syukur kepada Allah SWT atas limpahan nikmat sehat-Nya, baik itu berupa
sehat fisik maupun akal pikiran, sehingga saya mampu untuk menyelesaikan pembuatan makalah
sebagai tugas mata kuliah Sistem Penghantaran Obat ( SPO ).

Saya tentu menyadari bahwa makalah ini masih jauh dari kata sempurna dan masih banyak
terdapat kesalahan serta kekurangan di dalamnya. Untuk itu, saya mengharapkan kritik serta
saran dari pembaca untuk makalah ini, supaya makalah ini nantinya dapat menjadi makalah yang
lebih baik lagi. Kemudian apabila terdapat banyak kesalahan pada makalah ini saya mohon maaf
yang sebesar-besarnya.

Saya juga mengucapkan terima kasih kepada semua pihak khususnya kepada Dosen Mata
Kuliah Sistem Penghantaran Obat ( SPO ) saya yang telah membimbing dalam menulis makalah
ini.

Demikian, semoga makalah ini dapat bermanfaat. Terima kasih.

Semarang, 07 April 2020

Amaliyana Mega Dharma

ii
 BAB I

PENDAHULUAN

C. Latar Belakang

Solid Lipid Nanopartikel (SLN) adalah nanokarier yang dikembangkan sebagai

sistem penghantaran obat pengganti koloid sama hal nya dengan liposom, emulsi lipid,
nanopartikel polimer, dan sebagainya. Karena ukuran yang unik berdasarkan sifat dan
kemampuan untuk obat menggabungkan mereka, SLN memberikan kesempatan untuk
membangun prototipe terapi baru untuk system penghantaran obat dan penargetan. SLN
memiliki potensi besar untuk mencapai tujuan system penghantaran obat yang
ditargetkan dan dikendalikan, yang saat ini menarik minat para peneliti di seluruh dunia.
aspek-aspek yang berbeda dari SLN termasuk fabrikasi dan karakterisasi teknik,
formulasi variabel, rute administrasi, permukaan modifikasi, toksisitas, dan aplikasi
biomedis.
Solid Lipid Nanoparticle (SLN) telah muncul sebagai sistem penghantaran obat
generasi berikutnya dengan aplikasi potensial di bidang farmasi, kosmetik, penelitian,
pengobatan klinis dan ilmu lainnya. Baru-baru ini, perhatian yang meningkat difokuskan
pada SLN ini sebagai pembawa obat koloid untuk memasukkan obat hidrofilik atau
lipofilik. Protein dan antigen yang ditujukan untuk tujuan terapeutik dapat digabungkan
atau diserap ke SLN, dan selanjutnya diberikan melalui rute parenteral atau menjadi rute
alternatif seperti oral, nasal dan paru-paru. Hambatan yang terkait dengan kemoterapi
konvensional sebagian dapat diatasi dengan mengenkapsulasi mereka sebagai SLN.
Tinjauan saat ini berfokus pada kegunaan SLN dalam hal keuntungan, metodologi
produksi, karakterisasi dan aplikasinya. Jika diselidiki dengan benar, SLN dapat
membuka pemandangan baru dalam terapi penyakit kompleks.
Beberapa tahun terakhir ini, penerapan nanoteknologi di segala bidang
berkembang sangat pesat. Nanoteknologi merupakan bidang yang sangat multidisiplin,
mulai dari fisika terapan, ilmu material, sains, koloid dan antarmuka, fisika alat, kimia
supramolekul, mesin pengganda-diri dan robotika, teknik kimia, teknik mesin, rekayasa
biologi, dan teknik elektro. nanopartikel membuat para peneliti berlomba untuk
mendalami dan menerapkan teknologi ini pada bidangnya masing-masing, seperti
makanan, keramik, tekstil, kimia, farmasi dan kosmetik dan lain-lain.

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 BAB II

LANDASAN TEORI

D. Landasan Teori

Lipid nanopartikel padat (SLN) adalah dispersi koloid cair, yang matriksnya terdiri dari
lipida padat yang dapat terbiodegredasi. SLN terutama terdiri atas lipid yang berada pada fase
padat pada suhu ruang dan surfaktan pada emulsifikasi. Memiliki diameter rata-rata pada rentang
50 nm hingga 1000 nm pada aplikasi colloid drug delivery.

SLN memiliki sifat yang unik diantaranya ukuran yang kecil, luas permukaan yang besar,
loading drug yang besar, fase interaksi antarmuka, dan memiliki potensial untuk meningkatkan
performa farmasetika. Secara stuktural, SLN sedikit berbeda dengan nanopartikel bentuk
polimer. SLN tersusun dari lipid yang biokompatible terhadap tubuh dan bisa di buat tanpa
menggunakan pelarut organik.

Dengan formulasi khusus, SLN bisa membawa obat yang bersifat hidrofilik dan lipofilik.
SLN menggabungkan keuntungan dan menghindari kekurangan beberapa pembawa koloid
seperti kelas yang memiliki stabilitas fisik, perlindungan obat yang tidak stabil dari degradasi,
pelepasan terkontrol, tolerabilitas yang sangat baik.

Formulasi SLN untuk berbagai rute penggunaan (parenteral, kulit mulut, okular,
pulmonar, rektal) telah dikembangkan dan dicirikan secara menyeluruh secara in vitro dan in
vivo. Nanopartikel lipid padat memiliki matriks inti lipid padat yang dapat melarutkan molekul
lipofilik. Inti lipid distabilkan oleh surfaktan (pengemulsi). Untuk aplikasi farmasi, semua
formulasi eksipien harus memiliki status Umumnya Diakui sebagai Aman (GRAS).

Untuk mencapai dan mempertahankan partikel lipid padat pada saat pemberian, titik
lebur nanopartikel lipid harus melebihi suhu tubuh (37°C). Secara umum SLN dibuat dari
campuran lemak, surfaktan/emulsifier, dan air.

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 Lipid titik leleh tinggi yang diselidiki meliputi triasilgliserol (trigliserida), asilgliserol,
asam lemak, steroid, lilin, dan kombinasinya. Surfaktan yang diselidiki meliputi garam empedu
seperti sodium taurocholate, lipida membran biologis seperti lesitin, nonionik biokompatibel
seperti kopolimer etilena oksida/propilena oksida, ester sorbitan, etoksilat asam lemak, dan
campurannya.

Struktur Umum Dari Solid Lipid Nanopartikel ( SLN ).

C . Keuntungan dan Kerugian Solid Lipid Nanopartikel

a. Keuntungan

1. Meningkatkan bioavabilitas obat

2. Memproteksi obat yang sensitif terhadap lingkungan

3. Memiliki kemampuan pelepasan terkendali dan tertarget

4. Kemampuannya melindungi senyawa aktif dari penguraian oleh pengaruh faktor kimia
dan fisika

5. Mempunyai stabilitas, terutama stabilitas fisik yang lebih baik

6. SLN memiliki stabilitas yang lebih baik dibandingkan dengan liposom

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7. Memungkinkan produksi skala besar

8. Memungkinkan penggabungan obat-obat lipofilik dan hidrofilik

9. Penggunaan lokal, obat disempurnakan penetrasinya ke kulit melalui aplikasi dermal.

10. Bahan baku yang dibutuhkan sama dengan emulsi.

11. Bahan eksipien (lipid) yang murah

12. Dapat menghindarkan penggunaan pelarut organik yang umumnya toksik

b. Kerugian:

1. Adanya pertumbuhan partikel

2. Menyebabkan degredasi obat jika pembuatannya menggunakan tekanan tinggi dan

dapat terjadi fenomena gelasi yang menggambarkan perubahan viskositas dispersi
nanopartikel lipid padat dari viskositas yang rendah menjadi kental seperti gel.

3. Kemungkinan terjadinya transisi polimorfisme

4. Daya ikat yang lemah karena struktur kristaline lipida padatnya.

5. Rendahnya kapasitas untuk memuat obat hidrofilik karena efek partisi selama proses
produksi.

D. Karakteristik Solid Lipid Nanopartikel

Karakterisasi SLN diperlukan untuk pengendalian kualitasnya. Karakterisasi SLN

merupakan tantangan serius karena ukuran koloid partikel dan kompleksitas dan sifat
dinamik sistem pengiriman. Parameter yang harus dievaluasi: Ukuran partikel, potensial
zeta, pelepasan obat, morfologi permukaan. Polimorfisme, tingkat kristalinitas, skala
waktu proses distribusi.

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1. Ukuran Partikel Stabilitas fisik SLN tergantung pada ukuran partikelnya. Spektroskopi
korelasi foton (PCS) dan difraksi laser (LD) adalah teknik paling ampuh untuk penentuan
ukuran partikel. PCS (juga dikenal sebagai hamburan cahaya dinamis) mengukur
fluktuasi intensitas cahaya yang berserakan, yang disebabkan oleh pergerakan partikel.
Penentuan ukuran partikel dengan spektroskopi korelasi foton (PCS) mendeteksi kisaran
ukuran 3nm sampai 3μm dan dengan difraksi laser dalam kisaran ukuran 100 nm sampai
180 μm. Meskipun PCS adalah alat yang baik untuk mengkarakterisasi partikel nano,
namun mampu mendeteksi mikropartikel yang lebih besar (Pandey et al., 2005). Metode
LD didasarkan pada ketergantungan sudut difraksi pada ukuran partikel (spektrum
Fraunhofer). Partikel yang lebih kecil menyebabkan hamburan yang lebih kuat pada
sudut yang tinggi dibandingkan dengan yang lebih besar.

2. Zeta Potensial Pengukuran zeta potensial dapat dilakukan dengan menggunakan zeta
potential analyzer atau zetameter. Sebelum pengukuran, dispersi SLN diencerkan 50 kali
lipat dengan media preparasi dispersi asli untuk penentuan ukuran dan pengukuran zeta
potensial (Luo et al., 2006). Nilai zeta potensial yang lebih tinggi dapat menyebabkan
deagregasi partikel tanpa adanya faktor penyulit lainnya seperti stabilisator sterik atau

pelengkap permukaan hidrofilik. Pengukuran zeta potensial memungkinkan prediksi

tentang stabilitas penyimpanan dispersi koloid.

3. Mikroskop Elektron Scanning Electron Microscopy (SEM) dan Mikroskop Elektron

Transmisi (TEM) memberikan cara untuk mengamati secara langsung nanopartikel dan
karakterisasi fisik nanopartikel. TEM memiliki batas deteksi yang lebih kecil, adalah
validasi yang baik untuk metode lain dan orang harus menyadari ukuran sampel secara
statistik kecil dan efek yang dapat dimiliki oleh vakum pada partikel.

4. Static light scattering (SLS)/Fraunhofer Difraksi Metode ini mempelajari pola cahaya
yang berserakan dari larutan partikel dikumpulkan dan sesuai dengan persamaan
elektromagnetik fundamental dimana ukuran adalah variabel utama. Metode ini cepat dan
kasar, namun membutuhkan kebersihan lebih banyak daripada DLS, dan memajukan
pengetahuan tentang kualitas optik partikel.

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5. Dinamis Light Scattering (DLS) DLS, juga dikenal sebagai PCS atau Quasi-Elastic
Light Scattering (QELS) mencatat variasi intensitas cahaya yang tersebar pada skala
waktu mikrodetik. Variasi ini diakibatkan oleh gangguan cahaya yang tersebar oleh
partikel individual di bawah pengaruh gerak Brown, dan diukur dengan kompilasi fungsi
autokorelasi.

Kelebihan metode ini adalah kecepatan analisis, kurangnya kalibrasi dan sensitivitas yang
dibutuhkan terhadap partikel submikrometer. Keunggulan metode ini adalah kecepatan
analisis, kurangnya kalibrasi yang dibutuhkan, dan sensitivitas terhadap partikel
submikrometer.

6. Nuklir Magnetik Resonansi (NMR) NMR digunakan untuk menentukan ukuran dan
sifat nanopartikel. Selektivitas yang diberikan oleh pergeseran kimia melengkapi
kepekaan terhadap mobilitas molekuler untuk memberikan informasi mengenai status
fisikokimia komponen dalam partikel nano.

7. Atomic Force Microscopy (AFM)

Dalam teknik ini, tip probe dengan ketajaman skala atom direkayasa melintasi sampel
untuk menghasilkan peta topologi berdasarkan kekuatan yang ada di antara ujung dan
permukaan. Probe dapat diseret di seluruh sampel (mode kontak), atau diizinkan
melayang tepat di atas (mode kontak tidak), dengan sifat pastinya dari gaya tertentu yang
digunakan untuk membedakan di antara sub teknik. Resolusi yang sangat tinggi dapat
diperoleh dengan pendekatan ini, yang bersama dengan kemampuan untuk memetakan
sampel sesuai dengan sifat selain ukuran, misalnya daya tarik koloid atau ketahanan
terhadap deformasi, menjadikan AFM sebagai alat yang berharga (Mukherjee et al.,
2009)

8. Metode Akustik Spektroskopi akustik, mengukur redaman gelombang suara sebagai

alat untuk menentukan ukuran melalui persamaan fisik yang relevan. Selain itu, medan

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 listrik berosilasi yang dihasilkan oleh pergerakan partikel bermuatan di bawah pengaruh
energi akustik dapat dideteksi untuk memberikan informasi mengenai muatan
permukaan.

9. Difraksi X-Ray dan Differential Scanning Calorimetry (DSC) DSC dan X-ray
Diffractometry (PXRD) dilakukan untuk menentukan tingkat kristalinitas dispersi
partikel. Tingkat kristalinitas menggunakan DSC diperkirakan dengan membandingkan
entalpi pelebura/g bahan bulk dengan entalpi peleburan/g dispersi (Siekmann dan
Westesen, 1994).

E. Metode Solid Lipid Nanopartikel

Ada beberapa metode untuk memproduksi SLN seperti homogenisasi kecepatan tinggi
dan Ultrasonication, metode homogenisasi tekanan tinggi (High Pressure Homogenization/HPH)
atau homogenisasi kecepatan tinggi, sediaan SLN berbasis emulsi mikro, persiapan SLN dengan
menggunakan cairan superkritis, SLN dibuat dengan emulsifikasi pelarut/penguapan, metode
emulsi ganda dan metode pengeringan semprotan.

1. Teknik Homogenisasi Kecepatan Tinggi (High Speed Homo-Genization/HSH)

dan Ultrasonifikasi (Ultrasonication) Pembuatan SLN dengan metode HSH dan
ultrasonifikasi dilakukan dengan cara mendispersikan partikel pada tabung
ultrasound dengan kecepatan tinggi. Gabungan kedua metode ini sangat
sederhana dan bisa menguntungkan dibandingkan metode lain seperti
homogenisasi panas dan dingin karena peralatan yang digunakan dalam teknik
ini sangat umum di setiap laboratorium. Kerugiannya seperti mendistribusikan
ukuran partikel yang lebih besar mulai dari kisaran mikrometer menyebabkan
ketidakstabilan fisik seperti pertumbuhan partikel pada penyimpanan dan juga
kontaminasi logam akibat ultrasonication.
2. Metode Homogenisasi Tekanan Tinggi (High Pressure Homogenization/ HPH)
Metode HPH merupakan metode paling populer diantara metode-metode yang
sudah dikembangkan (Muller et.al., 2007).

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 Metode ini tidak hanya banyak dipakai oleh para peneliti bahkan juga banyak
diterapkan pada industri untuk menghasilkan SLN skala pabrik. Secara umum
tekanan diatur antara 100 bar hingga 2000 bar. Apabila memakai metode lain
untuk mendapatkan nanopartikel, kandungan lemak dalam formula tidak boleh
lebih dari 10%, akan tetapi dengan metode HPH kita dapat meningkatkan
kandungan lemak dalam formula sampai 40% (Menhnert, 2001).

3. Emulsifikasi dengan Pelarut/Evaporasi (Solvent Emulsification

(SE)/Evaporation) Pembuatan SLN dengan cara emulsifikasi adalah
dengan mengendapkan lemak yang sudah dicampurkan ke dalam o/w
emulsifier. Formula yang bersifat lipophilik kemudian dilarutkan didalam
air dan pelarut organik (seperti cyclohexane). Lalu pelarut organik
dievaporasi untuk mendapatkan lemak mikropartikel. Lemak
mikropartikel ini diendapkan lagi sampai dihasilkannya nanopartikel
(Sjostrom et.al., 1992). Dengan menggunakan metode ini Sjostrom
menghasilkan obat cholesterol acetat nanopartikel dengan ukuran antara
25 nm hingga 100 nm dengan emulsifier yaitu lecithin/sodium glyocholate.
Seperti yang sudah diterangkan diatas bahwa ukuran partikel yang
dihasilkan sangat dipengaruhi oleh perpaduan lemak dengan
surfaktan/emulsifier dan konsentrasi lemak dalam formula. Kelebihan dari
metode ini adalah tidak merusak bahan aktif karena proses produksi
dilakukan pada suhu rendah. Sementara kekurangan dari metode ini
adalah berdapak racun karena pemakaian pelarut organik.

4. Solvent Emulsification-Diffusion SLN juga dapat diproduksi dengan teknik

emulsifikasi-difusi pelarut. Ukuran partikel rata-rata tergantung pada
konsentrasi lipid dalam fase organik dan pengemulsi yang digunakan.
Partikel dengan diameter rata-rata 30-100 nm dapat diperoleh dengan teknik
ini. Menghindari panas selama pembuatan adalah keuntungan paling
penting dari teknik ini.

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 Di sini, matriks lipid dilarutkan dalam pelarut organik tak bercampur air
diikuti oleh emulsifikasi dalam fasa berair. Pelarut diuapkan di bawah tekanan
tereduksi sehingga terjadi dispersi nanopartikel yang dibentuk oleh presipitasi
lipid dalam medium berair (Muller et al., 2000 dan Trotta et al, 2003).

5. Pembuatan SLN Berbasis Mikroemulsi Pembuatan SLN berdasarkan

mikroemulsi Gasco dan rekan kerjanya (1997) mengembangkan SLN
berdasarkan pengenceran mikroemulsi. Ini dibuat dengan mengaduk campuran
transparan pada suhu 65-70°C yang biasanya terdiri dari asam lemak titik leleh
rendah seperti asam stearat, pengemulsi (misalnya polisorbat 20, polisorbat 60,
kedelaiaphosphatydylcholine dan garam natrium asam taurodeoksikolat),
pengemulsi co-emulsifier (misalnya butanol, sodium mono octylphosphate) dan
air. Mikroemulsi panas didispersikan dalam air dingin (2-3°C) dalam
pengadukan (Waghmare et al., 2012). Rasio volume tipikal mikroemulsi panas
terhadap air dingin berada pada kisaran 1:25 sampai 1:50. Proses pengenceran
sangat ditentukan oleh komposisi mikroemulsi. Dispersi SLN dapat digunakan
sebagai cairan granulasi untuk dipindahkan ke produk padat seperti tablet dan
pelet oleh proses granulasi, namun dalam kasus kandungan partikel rendah,
terlalu banyak air yang perlu dikeluarkan. Nanopartikel diproduksi hanya
dengan pelarut yang mendistribusikan dengan sangat cepat ke dalam fasa berair
(aseton), sementara ukuran partikel yang lebih besar diperoleh dengan pelarut
lipofilik lebih banyak (De Labouret et al., 1995).

6. Persiapan SLN dengan menggunakan cairan superkritis: Ini adalah teknik

baru yang baru-baru ini diterapkan untuk produksi SLN (Cavalli et al., 1996).
Cairan disebut superkritis saat tekanan dan suhu melebihi nilai kritis
masingmasing. Kemampuan cairan untuk melarutkan senyawa meningkat.

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 Teknologi ini terdiri dari beberapa proses untuk produksi nanopartikel seperti
perluasan cepat larutan superkritis (RESS), partikel dari gas larutan jenuh

(PGSS), pelarut aerosol ekstraksi pelarut (ASES), ekstraksi cairan superkritis

emulsi (SFEE).

Kelebihan teknik ini meliputi penghindaran penggunaan pelarut, partikel yang

diperoleh sebagai bubuk kering, bukan suspensi, memerlukan tekanan ringan
dan kondisi temporer. Larutan karbon dioksida 99,99% adalah pilihan yang
baik sebagai pelarut untuk metode ini (Chen et al., 2006).

7. Metode Emulsi Ganda Dalam metode ini, obat tersebut dienkapsulasi

dengan zat penstabil untuk mencegah pembagian obat ke fasa air eksternal
selama penguapan pelarut pada fasa air eksternal emulsi ganda w/o/w. Li et al.
(2010) membuat nanopartikel lipid padat yang dilengkapi dengan albumin
serum sapi (BSA) dengan menggunakan metode emulsi ganda.

8. Metode Pengeringan Semprotan Ini metode yang lebih murah daripada

liofilisasi. Metode ini menyebabkan agregasi partikel karena suhu tinggi, gaya
geser dan pencairan sebagian partikel. Hasil terbaik diperoleh dengan
konsentrasi SLN 1% dalam larutan trehalosa dalam air atau 20% trehalosa
dalam campuran etanolwater (10/90 v/v).

9. Teknik Injeksi Pelarut Di sini, lipid padat dilarutkan dalam pelarut pelarut
air. Campuran pelarut lipida disuntikkan ke dalam fase berair yang diaduk
dengan atau tanpa surfaktan. Akhirnya, dispersi disaring untuk menghilangkan
kelebihan lipid. Emulsi dalam fase berair membantu menghasilkan tetesan lipid
di tempat injeksi dan menstabilkan SLN sampai difusi pelarut selesai (Schubert
et al., 2003). Mishra dkk. (2010) SLN yang disiapkan dan dievaluasi
menggunakan metode injeksi Pelarut untuk pengiriman antigen permukaan
Hepatitis B untuk vaksinasi dengan menggunakan rute subkutan.

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F. Aplikasi Solid Lipid Nanopartikel

1. SLN Oral dalam Kemoterapi Anti Tuberkular Obat anti tuberkulosis seperti rifampsin,
isoniazid, pirazinamida dibuat sistem SLN terlarut mampu mengurangi frekuensi pemberian
dosis dan memperbaiki kepatuhan pasien. Obat antituberkulosis yang dilbuat SLN disiapkan
dengan menggunakan teknik pelarut difusi (Pandey et al., 2005).

2. SLN untuk Aplikasi Parenteral Wissing et al. (2004) secara intensif meninjau penggunaan
SLN secara parenteral. SLN sangat cocok untuk pengiriman sistemik karena mengandung bahan-
bahan yang dapat

ditoleransi secara fisiologis dan memiliki kemampuan penyimpanan yang baik setelah liofilisasi
dan/atau sterilisasi. Saat disuntikkan secara intravena, SLN cukup kecil untuk disirkulasikan
dalam sistem mikrovaskular dan mencegah pengambilan makrofag jika terjadi lapisan hidrofilik.
Oleh karena itu, SLN telah disarankan untuk penghantaran gen virus dan non-virus. SLN
kationik telah ditunjukkan untuk mengikat gen secara langsung melalui interaksi elektrostatik,
dan memiliki potensi manfaat dalam terapi gen yang ditargetkan dalam pengobatan kanker.
Partikel juga dapat dimodulasi melalui komposisi, sehingga memungkinkan pengikatan molekul
bermuatan berlawanan (Olbrich et al 2001; Tabatt et al., 2004; Pedersen et al 2006). Pengobatan
penyakit sistem saraf pusat seperti tumor otak, AIDS, gangguan neurologis dan psikiatri
seringkali terkendala oleh ketidakmampuan obat ampuh untuk melewati sawar darah otak
(BBB). Lapisan koloid hidrofilik meningkatkan pengangkutannya melalui BBB dan distribusi
jaringan (Kreuter 2001; Wang et al., 2002). Fundaro et al, 2000, menyiapkan silika stealth dan
SLF stealth tanpa templat dan mengandung stealth nanopartikel yang hadir dalam darah pada
konsentrasi yang lebih tinggi daripada SLN non-stealth setelah 24 jam setelah pemberian
intravena.

3. SLN untuk Aplikasi Topikal SLN dan NLC adalah sistem pembawa koloid yang sangat
menarik untuk aplikasi kulit karena berbagai efek yang diinginkan pada kulit selain karakteristik
sistem pembawa koloid. Sangat cocok digunakan pada kulit yang rusak atau meradang karena
didasarkan pada lipida non-iritan dan tidak beracun (Wissing and Muller 2003). Peniliti telah
melaporkan secara intensif aplikasi topikal SLN. Selama beberapa tahun terakhir, SLN dan NLC
telah dipelajari dengan senyawa aktif seperti Vitamin E, tocopherol asetat, retinol, ascorbyl
palmitate, clotrimazole, triptolide, phodphyllotoxin dan antiandrogen anti oksidan nonsteroid
58841 untuk aplikasi topikal. Area aplikasi yang baru ditemukan, baru ditemukan adalah
penggunaan SLN pada Krim Sunscreen (Waghmare et al., 2012).

11
4. SLN untuk Aplikasi Okular Pemberian obat okular melalui SLN telah dilaporkan beberapa
kali (Friedrich et al 2005). Kompatibilitas biologis dan sifat mukoadhesif SLN memperbaiki
interaksinya dengan mukosa okular dan memperpanjang waktu tinggal kornea obat, dengan
tujuan penargetan obat okular. Cavalli dkk., (2002) mengevaluasi SLN sebagai pembawa
pengiriman okular

tobramycin pada mata kelinci. Akibatnya SLN secara signifikan meningkatkan bioavailabilitas
obat dalam humor berair. Cavalli dkk., (1995) juga mempelajari pemberian pilocarpine melalui
SLN, yang biasa digunakan dalam pengobatan glaukoma, sebelumnya. Mereka melaporkan hasil
yang sangat mirip untuk meningkatkan bioavailabilitas okuler obat.

5. SLN sebagai Cosmeceuticals SLNs telah diterapkan dalam pembuatan tabir surya dan sebagai
agen pembawa aktif untuk tabir surya molekular dan blocker UV38. SLN dan NLCs telah
terbukti terkontrol merilis topikal oklusif inovatif. Lokalisasi yang lebih baik telah dicapai untuk
vitamin A di lapisan atas kulit dengan glyceryl behenate SLNs dibandingkan dengan formulasi
konvensional.

6. SLN dalam Kemoterapi Kanker Dari dua dekade terakhir beberapa agen kemoterapi telah
dienkapsulasi dalam SLN dan efikasi in vitro dan in-vivo telah dievaluasi. Tamoxifen, obat
antikanker telah dimasukkan ke dalam SLN untuk memperpanjang pelepasan obat berikut ini.
Pemberian pada kanker payudara (Murthy, 2005). Penargetan tumor telah dicapai dengan SLN
yang sarat dengan obat-obatan seperti metotreksat dan camptothecin. Suntikan lokal SLN
metoksantrone diformulasikan untuk mengurangi toksisitas dan meningkatkan keamanan dan
bioeffikasi obat dalam mengobati kanker payudara dan metastasis kelenjar getah bening (Wong
et al., 2006).

7. SLN untuk Aplikasi Rektal Beberapa laporan tersedia mengenai pemberian obat rektal via
SLN dalam literatur (Sznitowska et al., 2000). Sznitowska dkk., 2001 memasukkan diazepam ke
dalam SLN untuk pemberian rektal agar bisa memberikan tindakan cepat. Mereka menerapkan
dispersi SLN pada kelinci dan melakukan studi bioavailabilitas. Mereka menemukan bahwa
matriks lipid yang padat pada suhu tubuh bukanlah sistem yang menguntungkan untuk
pengiriman dubur diazepam. Mereka memutuskan untuk menggunakan lipid yang meleleh di
sekitar suhu tubuh dalam percobaan berikutnya. Daerah ini nampaknya sangat terbuka untuk
diselidiki, terutama bila manfaat rute rektal diperhitungkan. Lapisan PEG nampaknya merupakan
pendekatan yang menjanjikan pada pengiriman rektal dan akibatnya, peningkatan
bioavailabilitas.

12
8. SLN untuk Aplikasi Pernafasan Paru-paru menawarkan area permukaan yang tinggi untuk
penyerapan obat dengan menghindari efek first-pass. Penyerapan obat cepat dengan aerosolisasi
obat-obatan (dalam kisaran ukuran 1-3 μm) terjadi karena dinding alveoli di paru-paru dalam
sangat tipis (Agu et al., 2001; Banga 2003). Drainase limfatik memainkan peran penting dalam
pengambilan partikulat dalam sistem pernafasan. SLN dapat diusulkan sebagai pembawa obat
anti kanker dalam pengobatan kanker paru-paru atau obat peptida untuk meningkatkan
bioavailabilitas mereka. Penilaian distribusi radio SLN berlabel radioaktif telah dijelaskan dan
data menunjukkan serapan penting dan signifikan dari radio yang diberi label SLN ke dalam
limfatik setelah inhalasi (Videira et al., 2002). Dalam sebuah penelitian baru-baru ini, obat
antituberkulosis (rifampisin, isoniazid dan pirazinamida) dimasukkan ke dalam berbagai
formulasi partikel lipid padat yang berkisar dari 1,1-2,1 μm dan formulasi di nebulasi ke kelinci
percobaan melalui mulut untuk persalinan langsung (Pandey et al., 2005a dan 2005b). Nebulisasi
partikel lipid padat yang membawa obat antituberkulosis diamati berhasil meningkatkan
bioavailabilitas obat dan mengurangi frekuensi pemberian dosis untuk pengelolaan TB paru yang
lebih baik.

9. SLN untuk Aplikasi Nasal Pemberian nasal adalah rute pemberian obat alternatif non invasif
yang menjanjikan karena penyerapan cepat dan onset tindakan obat yang cepat, menghindari
obat labil (seperti peptida dan protein) di saluran GI dan transport yang tidak memadai melintasi
lapisan sel epitel (Lee et al. , 1994). Untuk meningkatkan penyerapan obat melalui mukosa
hidung, pendekatan seperti pengembangan formulasi dan turunan prodrug telah digunakan. SLN
telah diusulkan sebagai sistem pengiriman mukosa transgenik alternatif agen terapeutik
makromolekul dan diagnostik oleh berbagai kelompok penelitian (Muller dan Keck 2004; Prego
et al., 2005). Dalam sebuah laporan baru-baru ini, lapisan nanopartikel polimer dengan PEG
memberikan hasil yang menjanjikan sebagai pembawa vaksin (Vila et al., 2004). Peran lapisan
PEG dari nanopartikel asam polylactic dalam meningkatkan trans mukosa transportasi dari
molekul bioaktif yang dienkapsulasi dilaporkan berhasil oleh Tobio et al, 1998. Konsep ini bisa
bermanfaat bagi nanopartikel padat.

10. SLN untuk potensial pengaplikasian pertanian

Minyak atsiri yang diekstrak dari Artemisia arborescens L. saat digabungkan dalam SLN,
mampu mengurangi penguapan yang cepat dibandingkan dengan emulsi dan sistemnya telah
digunakan dalam pertanian sebagai pembawa pestisida ramah lingkungan yang sesuai (Lai et al.,
2006).

13
 pharmaceutics

Review
Solid Lipid Nanoparticles: Emerging Colloidal Nano
Drug Delivery Systems
Vijay Mishra 1 , Kuldeep K. Bansal 2, *, Asit Verma 1 , Nishika Yadav 1 , Sourav Thakur 1 ,
Kalvatala Sudhakar 1 and Jessica M. Rosenholm 2
1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India;
vijaymishra2@gmail.com (V.M.); asitverma234@gmail.com (A.V.); nishikayadav12345@gmail.com (N.Y.);
sourav.success.thkr@gmail.com (S.T.); ckbhaipharma@gmail.com (K.S.)
2 Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Abo Akademi University,
20520 Turku, Finland; jerosenh@abo.fi
* Correspondence: kuldeep.bansal@abo.fi




Received: 14 July 2018; Accepted: 26 September 2018; Published: 18 October 2018


Abstract: Solid lipid nanoparticles (SLNs) are nanocarriers developed as substitute colloidal drug
delivery systems parallel to liposomes, lipid emulsions, polymeric nanoparticles, and so forth.
Owing to their unique size dependent properties and ability to incorporate drugs, SLNs present an
opportunity to build up new therapeutic prototypes for drug delivery and targeting. SLNs hold
great potential for attaining the goal of targeted and controlled drug delivery, which currently draws
the interest of researchers worldwide. The present review sheds light on different aspects of SLNs
including fabrication and characterization techniques, formulation variables, routes of administration,
surface modifications, toxicity, and biomedical applications.

Keywords: solid lipid nanoparticles; cytotoxicity; targeted drug delivery; colloidal nanocarriers

1. Introduction
Solid lipid nanoparticles (SLNs) emerged in 1991 with the objective to provide biocompatibility,
storage stability and to prevent the incorporated drug from degradation [1]. SLNs, colloidal carriers of
nanoscopic size (50–1000 nm), made up of solid lipids (high melting fat matrix), are developed
to conquer the weaknesses (e.g., polymer degradation and cytotoxicity, lack of a suitable large
scale production method, inferior stability, drug leakage and fusion, phospholipid degradation,
high production cost, and sterilization problems) of traditional colloidal carriers, like polymeric
nanoparticles and liposomes [2]. SLNs show various distinctive features such as low toxicity, large
surface area, prolonged drug release, superior cellular uptake as compared to traditional colloidal
carriers as well as capability to improve solubility and bioavailability of drugs [3,4]. The release of drug
from SLNs depends on matrix type and drug location in the formulation. The SLNs fabricated from
biodegradable and biocompatible ingredients are able to incorporate both hydrophilic and lipophilic
bioactives and thus turning out to be a viable option for controlled and targeted drug delivery [4,5].
The solid core of SLNs is hydrophobic with a monolayer coating of phospholipids and the drug is
usually dispersed or dissolved in the core (Figure 1) [5–7].

Pharmaceutics 2018, 10, 191; doi:10.3390/pharmaceutics10040191 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2018, 10, 191 2 of 21
Pharmaceutics 2018, 10, x FOR PEER REVIEW 2 of 21

Figure
Figure1.1.General
Generalstructure
structureof
ofsolid
solidlipid
lipidnanoparticle
nanoparticle(SLN)
(SLN)loaded
loadedwith
withdrug.
drug.

1.1.Advantages
1.1. AdvantagesofofSLNs
SLNs

•• The cells of
The ofreticuloendothelial
reticuloendothelial system (RES)
system are unable
(RES) to take
are unable to up SLNs
take up because of their nanosize
SLNs because of their
range, thus
nanosize enabling
range, them to bypass
thus enabling them tospleen
bypassand liver and
spleen filtration [8,9]
liver filtration [8,9]
•• Provide high
Provide high stability
stability to
to incorporated
incorporated drugs
drugs
•• Feasibility
Feasibility of
of incorporating
incorporating both both hydrophilic
hydrophilic and
and lipophilic
lipophilic drugs
drugs
•• Improve
Improve bioavailability
bioavailability of of poorly
poorly water
water soluble
soluble molecules
molecules
•• Ease
Easein
in sterilization
sterilization and
and scale
scale up
up
•• Immobilizing
Immobilizing drug molecules within
drug molecules within solid
solid lipids
lipids provides
provides protection
protection from
from photochemical,
photochemical,
oxidative,
oxidative, and chemical degradation of sensitive drugs, with reduced chances of
and chemical degradation of sensitive drugs, with reduced chances of drug
drug leakage
leakage
•• Drying by lyophilization is achievable
Drying by lyophilization is achievable
• Provide opportunities for targeted and controlled release of drug
• Provide opportunities for targeted and controlled release of drug
• Biocompatible and biodegradable compositional ingredients [4]
• Biocompatible and biodegradable compositional ingredients [4]
1.2. Disadvantages of SLNs
1.2. Disadvantages of SLNs
• SLNs are compactly packed lipid matrix networks (ideal crystalline structure) having low space
• SLNs are compactly packed lipid matrix networks (ideal crystalline structure) having low space
for drug encapsulation, leading to poor drug loading capacity [10–13]
for drug encapsulation, leading to poor drug loading capacity [10–13]
• Various factors affect the loading or encapsulation of drugs in SLNs, such as interaction of drug
• Various factors affect the loading or encapsulation of drugs in SLNs, such as interaction of drug
and lipid melt, nature or state of lipid matrix, drug miscibility with lipid matrix, and the drug
and lipid melt, nature or state of lipid matrix, drug miscibility with lipid matrix, and the drug
being dispersed or dissolved in the lipid matrix
being dispersed or dissolved in the lipid matrix
• Chances of drug expulsion following polymeric transition during storage [14,15]
• Chances of drug expulsion following polymeric transition during storage [14,15]
• The dispersions have a high (70–90%) water content [16]
• The dispersions have a high (70–90%) water content [16]
1.3. Nanostructured Lipid Carriers
1.3. Nanostructured Lipid Carriers
Nanostructured lipid carriers (NLCs) are developed to conquer the difficulties of SLNs like drug
Nanostructured lipid carriers (NLCs) are developed to conquer the difficulties of SLNs like drug
expulsion and low drug loading, as NLCs are prepared from solid and liquid lipid mixture having
expulsion and low drug loading, as NLCs are prepared from solid and liquid lipid mixture having
non-ideal crystalline structure and prevent drug expulsion by avoiding crystallization of lipids [3].
non-ideal crystalline structure and prevent drug expulsion by avoiding crystallization of lipids [3].
NLCs consist of different spatial lipids (e.g., glycerides) and thus provide a larger distance between
NLCs consist of different spatial lipids (e.g., glycerides) and thus provide a larger distance between
the glycerides’ fatty acid chains and general unstructured crystal; and consequently, promote higher
the glycerides’ fatty acid chains and general unstructured crystal; and consequently, promote higher
drug accommodation. NLCs can be of three different types, viz. imperfect type, multiple type, and
amorphous type [16].
Pharmaceutics 2018, 10, 191 3 of 21

drug accommodation. NLCs can be of three different types, viz. imperfect type, multiple type, and
amorphous type [16].

• Imperfect type NLCs are prepared by mixing of solid lipids with small amounts of oils (liquid
lipids) and thus demonstrate high drug loading.
• In multiple type NLCs, the amount of oily lipids are higher, and therefore yields high drug
solubility as compared to solid lipids-. The reason of this phenomenon is based on the fact that
the solubility of lipophilic drugs in solid lipids are lower than the liquid lipids (oils).
• Amorphous type NLCs contain additional specific lipids e.g., isopropyl myristate, hydroxyl
octacosanyl, hydroxyl stearate etc. to avoid crystallization of solid lipid upon cooling. Thus,
expulsion of drug caused by crystallization of solid lipids could be prevented by amorphous type
NLCs [16].

NLCs have many advantages like: (a) dispersions of NLC by more solid content can be produced,
(b) high capacity of drug-loading as compared to SLNs, (c) modulating drug release profile can be
achieved with ease, (d) leakage of drug during storage is less than SLNs, and (e) production of final
dosage formulations (e.g., tablets, capsules) is feasible [17].

1.4. Lipid Drug Conjugates

Due to partitioning effects, the main problem with SLNs is poor loading of drugs. However,
highly potent hydrophilic drugs in low dose can suitably be incorporated in solid lipid matrix.
To overcome this difficulty, lipid drug conjugates (LDCs) were utilized, which displayed improvement
in drug loading capacities of SLN up to 33%. To produce LDC, first, insoluble drug-lipid conjugate
bulk is prepared by salt formation or via covalent linking. Then, it is processed with an aqueous
surfactant solution (e.g., Tweens) to prepare nanoparticles by high-pressure homogenization technique.
These types of matrices have shown potential in brain targeting of hydrophilic drugs in adverse
protozoal infections [18].

2. Compositional Profile of SLNs

Lipid and surfactant/stabilizer are the key components used to fabricate SLNs along with
co-surfactant, preservatives, cryoprotectant, and charge modifiers (Table 1). By reducing the interfacial
tension between the aqueous environment and the hydrophobic surface of the lipid core, surfactants
help in stabilizing the SLN structure [4,19].

Table 1. Ingredients used in SLNs-based formulations.

Ingredients Examples
Beeswax, Stearic acid, Cholesterol, Caprylic/capric triglyceride, Cetylpalmitate,
Glyceryl stearate (-mono, and -tri), Glyceryl trilaurate, Glyceryl trimyristate, Glyceryl
Lipid component
behenate (Compritol), Glyceryl tripalmitate, Hardened fat (Witepsol E85, H5 and W35),
Monostearate monocitrate, Solid paraffin, Behenic acid
Surfactant/Emulsifiers Phosphatidyl choline, Soy and Egg lecithin, Poloxamer, Poloxamine, Polysorbate 80
Sodium dodecyl sulphate, Tyloxopol, Sodium oleate, Taurocholate sodium salt,
Co-surfactant
Sodium glycocholate, Butanol
Preservative Thiomersal
Gelatin, Glucose, Mannose, Maltose, Lactose, Sorbitol, Mannitol, Glycine, Polyvinyl
Cryoprotectant
alcohol, Polyvinyl pyrrolidone
Dipalmitoyl phosphatidyl choline, Stearylamine, Dicetylphosphate, Dimyristoyl
Charge modifiers
phophatidyl glycerol

3. Fabrication Techniques of SLNs

Techniques such as High shear homogenization, Ultrasonication or High speed homogenization,
Cold homogenization, Hot homogenization, Microemulsion based methods, Supercritical fluid based
Pharmaceutics 2018, 10, 191 4 of 21

methods, Solvent
Pharmaceutics 2018, 10,emulsification/evaporation
x FOR PEER REVIEW methods, Double emulsion methods, and Spray drying 4 of 21
methods have been widely employed for the fabrication of SLNs [3,20].
3.1. High Shear Homogenization
3.1. High Shear Homogenization
In this technique, solid lipid nanodispersions are initially produced using high shear
In this technique,
homogenization. solid lipid
While handling of nanodispersions
the method is easy, are initially produced
the presence using high shear
of microparticles often
homogenization. While handling of the method is easy, the presence of microparticles
compromises the dispersion quality. Investigation of the effect of different process parameters such often
compromises
as stirring rate, thecooling
dispersion quality.
condition, andInvestigation of the
emulsification timeeffect of different
on zeta process
potential parameters
and particle such
size have
as stirring rate, cooling condition, and emulsification time on zeta potential and
been investigated. In a study, tripalmitin and mixtures of mono and tri-glycerides (WitepsolW35) particle size have
been
were investigated.
used as lipidsInwith a study, tripalmitin
glyceryl behenateand mixtures ofofmono
(monoester andand
glycerin tri-glycerides (WitepsolW35)
behenic acid) and Pluronic were
® F-
used as lipids with glyceryl behenate (monoester of glycerin and behenic acid) and Pluronic ® F-68
68 as steric stabilizers (0.5% w/w). Dispersions obtained with WitepsolW35 improved SLN quality by
as steric stabilizers
homogenizing at 20,000 w/w).
(0.5%rpm for Dispersions obtained
eight minutes. Cooling with
timeWitepsolW35
kept was 10improved SLNby
min followed quality
anotherby
homogenizing
phase of stirring at 20,000
at 5000 rpmrpmfor at
eight
roomminutes. Cooling[19].
temperature timeWhile
kept was
the 10 min followedindex
polydispersity by another
(PDI)
phase of stirring at 5000 rpm at room temperature [19]. While the polydispersity
increased at higher stirring rates, no significant change in particle size was observed. index (PDI) increased
at higher stirring rates, no significant change in particle size was observed.
3.2. Ultrasonication or High Speed Homogenization
3.2. Ultrasonication or High Speed Homogenization
Ultrasonication or high-speed stirring reduces the shear stress during SLN production.
Ultrasonication or high-speed stirring reduces the shear stress during SLN production. However,
However, some disadvantages are also associated with this method, such as physical instability due
some disadvantages are also associated with this method, such as physical instability due to
to agglomerates or bulky size particles and metal contamination by the high speed of homogenizer
agglomerates or bulky size particles and metal contamination by the high speed of homogenizer
in the SLNs formulation [3,4,21].
in the SLNs formulation [3,4,21].
3.3. Hot
3.3. Hot Homogenization
Homogenization
In this method,
In this method, aa pre-emulsion
pre-emulsion is created by
is created by the
the addition
addition of
of the
the lipid
lipid melt
melt containing
containing drug
drug and
and
aqueous emulsifier with the help of high shear mixing homogenizer at 500–1500 bar
aqueous emulsifier with the help of high shear mixing homogenizer at 500–1500 bar pressure, whichpressure, which
reduces the
reduces the size
size of
of the
the emulsion
emulsion globules.
globules. Minimum
Minimum fivefive cycles
cycles of
of homogenization
homogenization is is required to get
required to get
desired size of the globules. The colloidal hot oil in water emulsion is formed after homogenization,
desired size of the globules. The colloidal hot oil in water emulsion is formed after homogenization,
which upon
which upon cooling
cooling causes
causes thethe crystallization
crystallization of
of the
the lipid
lipid in globules and
in globules and leads
leads to the solid
to the solid lipid
lipid
nanoparticles (Figure
nanoparticles (Figure 2)2) [22].
[22].

Figure 2. Step by step procedure of hot homogenization technique.

Figure 2. Step by step procedure of hot homogenization technique.
3.4. Cold Homogenization
3.4. Cold Homogenization
Cold homogenization method has been adopted to overcome the problems associated with hot
Cold homogenization
homogenization, method hasdrug
such as accelerated beendegradation
adopted to overcome thetemperature
due to high problems associated
and losswith hot
of drug
homogenization,
into the aqueoussuch
phaseas due
accelerated drug degradation
to partitioning. However,due todrug
the high temperature
exposure to and loss of drug
temperature into
cannot
the aqueous phase due to partitioning. However, the drug exposure to temperature cannot
be eliminated completely in this method, due to drug solubilization in melted lipid and because be
eliminated completely in this method, due to drug solubilization in melted lipid and because of the
heat generation during the homogenization process. Therefore, the melt containing drug is cooled
rapidly using dry ice or liquid nitrogen. This rapid cooling forms the drug solid solution
(homogeneous distribution), which is subsequently pulverized to form microparticles by ball/mortar
Pharmaceutics 2018, 10, 191 5 of 21

of the heat generation during the homogenization process. Therefore, the melt containing drug is
Pharmaceutics
cooled 2018, using
rapidly 10, x FOR PEER
dry iceREVIEW
or liquid nitrogen. This rapid cooling forms the drug solid solution 5 of 21
(homogeneous distribution), which is subsequently pulverized to form microparticles by ball/mortar
milling. These
milling. These microparticles
microparticles are are dispersed
dispersed in chilled aqueous
in chilled aqueous phase
phase containing
containing emulsifier
emulsifier and
and
homogenized subsequently at room temperature for the even allocation of drug in the
homogenized subsequently at room temperature for the even allocation of drug in the lipid matrix [4].lipid matrix
[4]. Particle
Particle sizessizes attained
attained by this
by this technique
technique are usually
are usually inrange
in the the range of 50–100
of 50–100 nm [23].
nm [23].

3.5. Microemulsion
3.5. Microemulsion Based
Based Method
Method
This technique
This technique involves
involves dilution
dilution ofof aa microemulsion
microemulsion to to precipitate
precipitate the
the lipid.
lipid. SLNs
SLNs areare produced
produced
by stirring an optically transparent mixture containing a low melting fatty
by stirring an optically transparent mixture containing a low melting fatty acid, an emulsifier, acid, an emulsifier, co-
emulsifiers andand
co-emulsifiers water
waterat 65–70
at 65–70 ◦
°C. After that,that,
C. After the hot
themicroemulsion is dispersed
hot microemulsion in coldinwater
is dispersed under
cold water
stirring. The volume ratios of the hot microemulsion to cold water usually are
under stirring. The volume ratios of the hot microemulsion to cold water usually are in the range ofin the range of 1:25 to
1:50.toThe
1:25 dilution
1:50. process
The dilution is critically
process determined
is critically by theby
determined composition of theofmicroemulsion
the composition the microemulsion [19]. This
[19].
microemulsion
This microemulsion is then dispersed
is then dispersedin aincold
a coldaqueous
aqueous medium
mediumunder
undermild
mildmechanical
mechanical mixing, which
mixing, which
leads to
leads to precipitation
precipitation ofof the
the lipid
lipidphase
phasein intotoSLNs.
SLNs. The
The method
method isisrepresented
representedin inFigure
Figure3.3.

Figure 3. Schematic
Figure 3. Schematic representation
representation of
of SLN
SLN production
production by
by microemulsion
microemulsion technique.
technique.

3.6. Supercritical Fluid Based Method

3.6. Supercritical Fluid Based Method
In this method, SLNs are prepared by particles from gas saturated solutions (GSS), thereby
In this method, SLNs are prepared by particles from gas saturated solutions (GSS), thereby
providing the advantage of solvent-less processing. SLN can be organized by using the fast expansion
providing the advantage of solvent-less processing. SLN can be organized by using the fast expansion
of supercritical carbon dioxide solutions [8]. GSS helps in melting the lipid material, whereafter the
of supercritical carbon dioxide solutions [8]. GSS helps in melting the lipid material, whereafter the
lipid melt along with GSS will dissolve in the super critical fluid (SCF) under pressure. The saturated
lipid melt along with GSS will dissolve in the super critical fluid (SCF) under pressure. The saturated
solution is sprayed through the nozzle or atomizer, which causes the expansion of solution whereby
solution is sprayed through the nozzle or atomizer, which causes the expansion of solution whereby
SCF escapes rapidly leaving behind the fine dry lipid particles. Absence of organic solvents and wide
SCF escapes rapidly leaving behind the fine dry lipid particles. Absence of organic solvents and wide
range miscibility of lipids in SCF justify the advantage of this technique [14].
range miscibility of lipids in SCF justify the advantage of this technique [14].
3.7. Solvent Emulsification Evaporation Method
3.7. Solvent Emulsification Evaporation Method
Solvent emulsification evaporation method (SEE) has three basic steps for preparation of
Solvent emulsification
nanoparticles. In step (I), lipid evaporation
material is method
added to(SEE) has volume
a known three basic steps solvent
of organic for preparation
and mixed of
nanoparticles.
properly In astep
to yield (I), lipid material
homogenous is added
clear solution to a known
of lipid. In step volume of prepared
(II), above organic solvent
solutionand mixed
is added
properly to yield a homogenous clear solution of lipid. In step (II), above prepared
to the right volume of water in order to form a coarse emulsion by using high-speed homogenizer. solution is added
to the right volume
Nanoemulsion is thenof obtained
water in in order
stepto(III)
form
by ausing
coarse emulsion byhomogenizer,
high-pressure using high-speedwhichhomogenizer.
convert the
Nanoemulsion
coarse emulsionisintothena obtained
nanoemulsionin stepdue
(III)toby using
high high-pressure
pressure, resulting homogenizer,
in breakdown which convert
of the the
globules.
coarse emulsion into a nanoemulsion due to high pressure, resulting in breakdown
After nanoemulsion formation, it is kept overnight under continuous stirring on a magnetic stirrer or of the globules.
Afterinnanoemulsion
kept a hood to remove formation, it isof
the traces kept overnight
organic under
solvent. continuous stirring
Nanodispersion on aafter
is formed magnetic stirrer of
evaporation or
kept in a hood to remove the traces of organic solvent. Nanodispersion is formed
organic solvent, as lipid material will precipitate in the water. The precipitation of lipids in aqueous after evaporation
of organicissolvent,
medium separated as lipid
out by material
filteringwill precipitate
through in the
sintered water.
disc filterThe precipitation
funnel. of lipids
Nanoparticles in aqueous
prepared by
medium is separated out by filtering through sintered disc filter funnel. Nanoparticles prepared by
this strategy are nanosized, non-flocculated (single entity) and have high entrapment efficiency
[24,25]. The layout of this method is given Figure 4.
Pharmaceutics 2018, 10, 191 6 of 21

this strategy are nanosized, non-flocculated (single entity) and have high entrapment efficiency [24,25].
The layout of
Pharmaceutics this
2018, 10,method is given
x FOR PEER REVIEWFigure 4. 6 of 21

Figure 4. Flow chart for solvent emulsification/evaporation method.

Figure 4. Flow chart for solvent emulsification/evaporation method.
3.8. Double Emulsion Method
3.8. Double Emulsion Method
Double emulsion technique is one of the most frequently used techniques to prepare nanoparticles
Double with
encapsulated emulsion technique
hydrophilic drugsisusing
one stabilizer
of the most frequently agent
or surface-active used [26].
techniques to prepare
This method is also
nanoparticles encapsulated with hydrophilic drugs using stabilizer or surface-active
known as multiple emulsion method, where it has three basic steps: (i) formation of the water agent [26].inThis
oil
method isoralso
emulsion known
inverse as multiple
emulsion, emulsion
(ii) addition method,
of the W1 /Owhere it has
emulsion three
into basic steps:
the aqueous (i) formation
solution of polymerof
thesurfactant
or water in oil emulsion
to form or inverse
a W1 /O/W emulsion, (ii) addition of the W1/O emulsion into the aqueous
2 emulsion with continuous stirring (sonication or homogenization),
solution of polymer or surfactant to form
and (iii) evaporation of the solvent or filtration a W1/O/W 2 emulsion with continuous stirring (sonication
of the multiple emulsion to form the nanoparticles.
or homogenization),
The double emulsion and (iii) evaporation
technique of thesized
produces larger solvent or filtration
particles, of the multiple
than surface emulsion
modification to form
is achievable
through this technique by incorporating hydrophilic polymers such as PEG during step ii [27].surface
the nanoparticles. The double emulsion technique produces larger sized particles, than
modification is achievable through this technique by incorporating hydrophilic polymers such as
3.9.
PEGSpray Drying
during Method
step ii [27].
The spray drying method is an alternative procedure to transform an aqueous SLN dispersion
3.9. Spray Drying Method
into a drug product. This method is barely used for formulation of SLNs; however, it is cheaper than
The spray Particle
lyophilization. drying method is an due
aggregation alternative
to high procedure
temperatureto and
transform an aqueous
shear force, SLN dispersion
and partial melting of
into a drug product. This method is barely used for formulation of SLNs; however, it is cheaper
the particles are drawbacks associated with this method [24]. This method requires lipids that have than
a
lyophilization.
melting Particle
point above ◦
70 aggregation
C [28]. due to high temperature and shear force, and partial melting of
the particles are drawbacks associated with this method [24]. This method requires lipids that have a
4. Drying
melting Techniques
point above 70of °CSLNs
[28].

4.1. Spray Drying

4. Drying Techniques of SLNs
A redispersable powder can be obtained by spray drying, following general requirements of
4.1. Spray
intravenous Drying
injections. Addition of carbohydrates and lower amount of lipid during spray drying
favorAthe
redispersableofpowder
shielding the colloidal
can beparticles.
obtained Lipid melting
by spray canfollowing
drying, be reduced, usingrequirements
general ethanol–water
of
mixtures (dispersion
intravenous medium)
injections. rather
Addition than pure water
of carbohydrates duelower
and to low inlet temperatures.
amount It was
of lipid during suggested
spray drying
that
favorfor theshielding
the optimumofresult, SLN concentrations
the colloidal of 1%
particles. Lipid in solution
melting can beof reduced,
30% trehalose
usinginethanol–water
water or 20%
trehalose in ethanol–water mixtures (10/90 v/v) could be used [29].
mixtures (dispersion medium) rather than pure water due to low inlet temperatures. It was suggested
that for the optimum result, SLN concentrations of 1% in solution of 30% trehalose in water or 20%
trehalose in ethanol–water mixtures (10/90 v/v) could be used [29].
Pharmaceutics 2018, 10, x FOR PEER REVIEW 7 of 21
Pharmaceutics 2018, 10, 191 7 of 21
4.2. Lyophilization
Lyophilization increases the physical and chemical stability of SLN over prolonged storage
4.2. Lyophilization
times. Furthermore, it prevents degradation responses and preserves the initial particle size. SLN
Lyophilization increases the physical and chemical stability of SLN over prolonged storage times.
ingredients are required for adequate chemical strength and narrow size distribution of particles to
Furthermore, it prevents degradation responses and preserves the initial particle size. SLN ingredients
circumvent crystal growth. The SLN formulation should be unaffected by temperature variations
are required for adequate chemical strength and narrow size distribution of particles to circumvent
during shipping. It has been shown that in aqueous SLN dispersions, particle sizes have not
crystal growth. The SLN formulation should be unaffected by temperature variations during shipping.
undergone alteration over several months. Lyophilization involves surfactant protective effect.
It has been shown that in aqueous SLN dispersions, particle sizes have not undergone alteration over
However, the lipid content of SLN dispersion should not exceed 5% for avoiding the increase in
several months. Lyophilization involves surfactant protective effect. However, the lipid content of
particle size [29].
SLN dispersion should not exceed 5% for avoiding the increase in particle size [29].
5. Characterization Techniques of SLNs
5. Characterization Techniques of SLNs
Various parameters need to be assessed to understand the fate of SLNs, such as size, particle size
Various parameters need to be assessed to understand the fate of SLNs, such as size, particle size
distribution, zeta potential, nature and degree of crystallinity, lipid alteration due to polymorphism
distribution, zeta potential, nature and degree of crystallinity, lipid alteration due to polymorphism
nature, surface morphology, as well as existence of other colloidal structures (micelles, supercooled
nature, surface morphology, as well as existence of other colloidal structures (micelles, supercooled
melts, and drug nanoparticles) [30].
melts, and drug nanoparticles) [30].

5.1.
5.1. Particle
Particle Size
Size and
and Zeta
Zeta Potential
Potential
Particle
Particle size,
size, polydispersity
polydispersity indexindex (PDI)
(PDI) andand zeta
zeta potential
potential are the essential
are the essential characteristics
characteristics ofof
nanoparticles
nanoparticles [9]. Dynamic light scattering (DLS) is one of the most important techniques used
[9]. Dynamic light scattering (DLS) is one of the most important techniques used toto
characterize
characterize SLNs.
SLNs. TheThe speed
speed ofof analysis,
analysis, easy
easy sample
sample preparation,
preparation, andand sensitivity
sensitivity toto submicrometer
submicrometer
particles
particles are the advantages
are the advantages of this method
of this method [30].[30]. The
The size
size of
of SLNs
SLNs is is an
an important
important factor
factor for
for their
their
physical stability [31]. Zeta potential measurements can provide information
physical stability [31]. Zeta potential measurements can provide information about the colloidal about the colloidal
stability
stability of
of the
the particles
particles as as well
well asas shelf
shelf life of colloidal
life of colloidal dispersions.
dispersions. As As aa rule
rule of
of thumb,
thumb, high values
high values
of zeta potential (e.g., greater than ±30 mV) can stabilize the colloidal dispersion
of zeta potential (e.g., greater than ±30 mV) can stabilize the colloidal dispersion by electrostatic by electrostatic
repulsion
repulsion under
under given
given conditions
conditions (Figure
(Figure 5)5) [30].
[30]. Electrostatic
Electrostatic repulsion
repulsion causes
causes the
the particles
particles to
to repel
repel
each
each other, thus avoiding aggregation (Figure 5C,D). However, particles with zeta potential near zero
other, thus avoiding aggregation (Figure 5C,D). However, particles with zeta potential near zero
under
under storage
storage conditions
conditionsmay mayalsoalsobebestabilized
stabilizedupon uponstorage.
storage.Such
Suchstabilization
stabilizationcancan
be be
achieved
achieved by
coating
by coatingthethe
particle
particlewithwitha hydrophilic
a hydrophilic polymer
polymer(e.g.,(e.g.,PEG)
PEG)totocreate
createaa physical
physical barrier against
barrier against
aggregation.
aggregation. This stabilization is known as steric stabilization (Figure 5B). The appropriateness of
This stabilization is known as steric stabilization (Figure 5B). The appropriateness of
nanocarrier
nanocarrier formulations
formulations regarding
regarding specific
specific route
route ofof drug
drug administration
administration is is largely
largely based
based onon the
the size,
size,
size
size distribution
distribution andand colloidal
colloidal stability.
stability. Their
Their control
control and
and validation
validation are
are thus
thus ofof high
high importance
importance for for
efficient clinical prospects of nanocarrier preparations
efficient clinical prospects of nanocarrier preparations [32]. [32].

Figure 5. Influence of zeta potential on particle-particle interaction.

Figure 5. Influence of zeta potential on particle-particle interaction.
Pharmaceutics 2018, 10, 191 8 of 21

5.2. Surface Morphology

Electron microscopy techniques such as scanning electron microscopy (SEM) gives 3D images
of the particles, surface morphology, and transmission electron microscopy (TEM) gives information
about the size and shape of nanoparticles as well as internal structure [33].

5.3. Degree of Crystallinity

Degree of crystallinity of lipid particles can be determined with the aid of differential scanning
calorimetry (DSC). It is a thermo-analytical technique, which delivers a fast and accurate method for
determining the degree of crystallinity of lipids based on the enthalpy of the lipid. Powder X-ray
diffractometry (PXRD) is another non-destructive method and widely applied for the description of
crystalline materials, and analyze the crystal structure of the SLN [23].

5.4. Acoustic Methods

Acoustic spectroscopy is another technique, which measures the attenuation of sound waves as a
mean of determining size and surface charge by fitting physically relevant equations. The acoustic
energy is applied to the nanoparticles, which introduces charge to the particles because of the
movement and generation of the oscillating electric field. Thus generated electric field is utilized to
describe the surface charge information [20].

6. Scale-Up of SLNs Production

Gasco and co-workers designed an apparatus to fabricate SLNs, which permits dispersion of
warm microemulsion in cold water for quick production of larger amounts of SLNs [34]. This apparatus
consists of:

• Thermostated aluminum chamber (syringe) containing pneumatically functioned piston for

delivering the microemulsion at a designated flux.
• At the bottom of the aluminum chamber, there is a stainless steel support for a sterile membrane
filter (0.22 µm), to assure the sterility of the product.
• The stainless steel support is connected with a needle by Lure Lock connection. This apparatus is
placed in an electric thermostated jacket. SLNs are formed by dispersing the warm microemulsion
into an ice-cooled capsule containing water. The water is stirred by a cylindrical magnetic bar at a
fixed rate (300 rpm).
• The microemulsion drops from the needle in the center of the capsule (ice-cooled). The SLN
dispersion is stirred for additional 15 min after the widespread microemulsion dripping.

The process factors such as pressure applied to the pneumatic cylinder, needle gauge, temperature
of the aluminium chamber, and volume of dispersing water primarily affect the particle size and PDI
of SLNs. A temperature difference between warm microemulsion and cold dispersing water plays an
important role on the resulting size of the produced SLNs. A rapid crystallization of the oil droplets of
the warm microemulsion during quenching favors the formation of small SLNs and avoids coalescence.
By the use of a small needle, as well as high pressure and temperature, the SLNs with diameter of
about 26 nm, and PDI of 0.1 were obtained [34].
Gohla and Dingler standardized a scaling and production method to manufacture drug free
and drug loaded SLNs on medium scale. SLN batches of 2–10 kg were produced by high pressure
homogenization technique using a modified Lab 60 device by discontinuous mode. For 50 kg batches,
a continuous production mode was used by combining two homogenizers in series. A Gaulin 5.5
device was chosen as first homogenizer to transport the SLN dispersion into the Lab 60 device as a
second homogenizer. Homogenization at 500 bar pressure was found to be the ideal pressure condition
with 2–3 cycles. The authors demonstrated that production of SLNs can be easily scaled up to industrial
scale [3,35].
 Pharmaceutics 2018, 10, 191 9 of 21
Pharmaceutics 2018, 10, x FOR PEER REVIEW 9 of 21

7.7.Drug
DrugLoading
Loadingand
andRelease
ReleaseAspects
Aspectsof
ofSLNs
SLNs

7.1.Drug
7.1. DrugLoading
Loadinginto
intoSLNs
SLNs
Currently, the
Currently, the fabrication
fabrication strategy
strategyofof lipid
lipid nanocarriers
nanocarriersforfor controlled
controlled and
and stimuli-responsive
stimuli-responsive
drug release has raised research attention for overcoming the problems
drug release has raised research attention for overcoming the problems associated with associated with poorly
poorly
soluble and toxic drugs. There are mainly three drug incorporation models
soluble and toxic drugs. There are mainly three drug incorporation models valid for SLNs: valid for SLNs:
Homogenousmatrix
Homogenous matrixmodel,
model, Drug
Drug enriched
enriched shell-core
shell-core shellshell
model,model, and Drug
and Drug enriched
enriched core-core
core-core shell
shell model (Figure 6)
model (Figure 6) [36–38]. [36–38].

Figure 6. Models of incorporation of active compounds into SLN.

Figure 6. Models of incorporation of active compounds into SLN.
In homogenous matrix model, the core may consist of drug in either amorphous clusters or
molecularly dispersed
In homogenous phase.
matrix Thisthe
model, model
core ismay
usually observed
consist of drugwhen highly
in either lipophilicclusters
amorphous drugs are
or
incorporated into SLN either by application of hot or cold homogenization
molecularly dispersed phase. This model is usually observed when highly lipophilic drugs are method.
In drug into
incorporated enriched
SLN shell
eithermodel, drug is available
by application of hot ornear
coldthe shell, thus yielding
homogenization a drug free lipid core.
method.
A phase
In drugseparation
enrichedoccurs
shellwhen
model,thedrug
solution is coolednear
is available andthelipid precipitates
shell, out leading
thus yielding a drugtofree
drug free
lipid
lipid core. During the same period, the drug re-partitions into the remaining
core. A phase separation occurs when the solution is cooled and lipid precipitates out leading to liquid-lipid phase and
drugfree
drug gradually increases
lipid core. Duringits the
concentration
same period, in the
theouter
drugshell of the lipid
re-partitions intocore.
the remaining liquid-lipid
phaseAand drug-enriched coreincreases
drug gradually can be formulated by liquefying
its concentration in the drug
outerinshell
the lipid
of thetolipid
its saturation
core. solubility
whereby a nanoemulsion is formed. Supersaturation of the drug in lipid melt occurs
A drug-enriched core can be formulated by liquefying drug in the lipid to its saturation solubility during the cooling
of the nanoemulsion
whereby a nanoemulsion and iscauses precipitation
formed. of the drug
Supersaturation of the before
drugthe in precipitation
lipid melt occursof lipid. Further
during the
cooling will lead not only to drug but also lipid precipitation surrounding
cooling of the nanoemulsion and causes precipitation of the drug before the precipitation of lipid.the drug precipitation,
which will
Further act aswill
cooling a membrane
lead nottowards
only toincorporated
drug but also druglipid
[39]. precipitation surrounding the drug
precipitation, which will act as a membrane towards incorporated drug [39].
7.2. Drug Release from SLNs
For Release
7.2. Drug any formulation,
from SLNs the drug release mechanism is of utmost importance. Drug release from
SLNs is attributed by degradation, erosion, or diffusion. The release mechanism of drug from SLN
For any formulation, the drug release mechanism is of utmost importance. Drug release from
matrix depends on the lipid and its composition. In SLN, drug is either embedded in the matrix or
SLNs is attributed by degradation, erosion, or diffusion. The release mechanism of drug from SLN
on the surface, and such a system can show versatile release or dual release (immediate release with
matrix depends on the lipid and its composition. In SLN, drug is either embedded in the matrix or
sustained release). Drug adhered on the surface of SLN will disperse from the nanoparticle and will
on the surface, and such a system can show versatile release or dual release (immediate release with
show an immediate release effect, thereafter the matrix can erode or degrade depending upon the lipid
sustained release). Drug adhered on the surface of SLN will disperse from the nanoparticle and will
composition, and release the drug in a controlled manner. Temperature or surface-active agents can
show an immediate release effect, thereafter the matrix can erode or degrade depending upon the
control drug solubility in water. Temperature based drug release or high amount of surfactant can
lipid composition, and release the drug in a controlled manner. Temperature or surface-active agents
cause burst release of drug from SLN [40]. Thus, the production of the SLN is usually takes place at
can control drug solubility in water. Temperature based drug release or high amount of surfactant
can cause burst release of drug from SLN [40]. Thus, the production of the SLN is usually takes place
at room temperature to avoid burst release and partition of drug in aqueous phase. This can lead into
Pharmaceutics 2018, 10, 191 10 of 21

room temperature to avoid burst release and partition of drug in aqueous phase. This can lead into
partitioning of majority of drug in lipid phase and, therefore, a sustained or controlled release without
any immediate release of drug can be observed from SLN. The common ideology of drug release
from SLNs depicts that the release is affected by particle size. Smaller particles with large surface area
provide rapid drug release as compared to larger particles. Further, drug release also depends on the
type of drug entrapment model of SLN, for example, faster drug release can be observed with drug
enriched shell model.
Venkateswarlu and Manjunath have performed in vitro release studies on SLN containing
clozapine. Release of clozapine followed Weibul and Higuchi equations rather than the first order
equation. Drug properties can influence the release via parameters governing the release such as drug
solubility (water or lipid soluble), and its interaction with the lipid matrix. Influence of temperature at
the time of production can cause solublization of drug in water as the high enthalpy will dissolve the
drug, which can lead to deposition of drug on the outer surface of the lipid matrix [41].
SLNs have also been tuned to provide drug release in response to external or internal stimuli.
Using the concept of solid-liquid transition upon heating, thermoresponsive SLNs have been recently
reported. A mixture of lipids (lauric acid and oleic acid, lauric acid, and linoleic acid) was used in this
study to fabricate SLNs. Drug release study demonstrated rapid release of loaded 5-fluorouracil (>90%)
at 39 ◦ C attributed to the melting of lipid core, whereas 22–34% of drug release was observed at 37 ◦ C
due to the solid core [42]. In another study, cholesterol-PEG coated SLNs have been investigated for its
pH sensitive drug release pattern. These particles show faster drug release of loaded doxorubicin at
pH 4.7 compared to pH 7.4. Depletion of electrostatic attractions between the negatively charged lipid
core lauric acid (due to its protonation) and the positively charged doxorubicin was suggested to be
responsible for accelerated release at low pH [43].

8. Routes of Administration for SLNs

8.1. Topical Route

SLNs are commonly used in topical applications due to their biocompatible nature [44]. Lipophilic
drug loaded in SLN displayed higher penetration through skin compared to free drug, due to higher
exclusivity and hydration of stratum corneum [45]. Upon application, SLNs gradually transform to
the stable polymorph and sustained release can be observed. If such polymorphic transitions are
controlled by the addition of a surface-active agent, then controlled release of drug from SLNs can be
observed [46,47].

8.2. Pulmonary Route

Pulmonary route has the capacity to deliver drugs in a non-invasive manner with the help of
some device or inhaler to reach the systemic circulation, bypassing first pass metabolism or to treat
some lung related diseases. Lipid nanoparticle systems are useful in enhancing drug absorption and
transport efficacy in alveolar macrophages in the treatment of diseases related to lungs or non-lung
diseases [48].

8.3. Oral Route

Delivering SLNs through oral route is very easy and can be delivered in suspension form or
solid dosage forms such as a tablet, capsule or dry powder. Lopinavir loaded SLNs were developed
by Negi et al. to improve the bioavailability of the drug. Lopinavir loaded SLNs were prepared by
means of hot self nano-emulsification method. Due to high intestinal lymphatic uptake of drug-SLNs,
the lopinavir oral bioavailability was substantially increased [49].
Silva et al. prepared risperidone loaded SLNs for oral delivery and analyzed them for stability,
drug release and improvement of bioavailability [50]. Singh et al. developed rifampicin loaded SLN to
Pharmaceutics 2018, 10, 191 11 of 21

prevent the hydrolysis of drug in acidic pH. This approach not only prevents the degradation of drug,
but also abridges the intimidation of therapy failure [51,52].

8.4. Intravenous Administration

Intravenous (i.v.) injection is the most studied route of administration for SLNs, particularly for
targeted delivery. Yang et al. reported the pharmacokinetics and biodistribution of camptothecin
loaded SLN after i.v. injection in mice. In comparison to a neat drug solution, SLNs were found to
enhance AUC/dose and mean residence times (MRT) especially in brain. The highest accumulation of
SLN in brain, compared to free drug among the tested organs, suggested brain targeting potential of
this carrier [53].

8.5. Ocular Delivery

SLNs showed good permeation property for ocular delivery. The drug release can be sustained
or controlled onto the ocular mucosa, which increased the pre-corneal retention time of the drug as
compared to conventional ophthalmic solutions [54–58]. Moreover, nanoscopic size of SLN does not
cause any blurred vision. However, SLNs aimed for ocular delivery should have to meet specific
criteria, like ocular compatibility (Draize rabbit eye test), sterility, isotonicity, and pH value (similar to
lachrymal fluid) [59].
Khurana et al. employed quality by design (QbD) approach (encouraged by regulatory bodies for
improvement of finished product quality) for developing a moxifloxacin ocular nanosuspension.
The SLNs prepared by high pressure homogenization technique exhibited sustained release of
moxifloxacin from an in-situ gelling system [60].

9. Protection of Incorporated Bioactives from Environmental Degradation in SLNs

SLNs contain bioactives inside the core, thus avoid the direct contact of drug with the external
environment, and increase the incorporated drug stability. SLNs markedly improve the stability
of siRNA, peptides, and proteins by providing protection against proteolytic degradation and may
subsequently provide their sustained release [61].
SLNs act as a cage for protecting acid labile drugs from gastric acid degradation. Arteether
endoperoxide ring is an antimalarial drug that degrades in gastric acidic medium, which limits it use.
However, it was demonstrated that its degradation could be circumvented by incorporating into SLNs,
which consequently retained the activity of the drug [62]. SLNs have also been used to stabilize and
deliver a DNA vaccine against visceral leishmaniasis [63].

10. Surface Modifications of SLNs

Surface engineering of SLNs improves biocompatibility and targetability. Wang et al. developed
hyaluronic acid (HA) decorated, Pluronic 85 (P85) coated paclitaxel (PTX) loaded SLN (HA-PTX-
P85-SLN) to overcome drug resistance and to increase antitumor efficacy. The SLNs prepared by hot
homogenization technique showed a mean diameter of 160 nm and PTX loading content of 4.9%. PTX
loaded SLN demonstrated sustained drug release compared to free PTX. This study suggested that
HA modified SLN increased tumor accumulation and thus significantly inhibited PTX resistant tumor
growth [64].
Recently, Baek et al. modified the SLN surface by coating N-carboxymethyl chitosan (NCC) for
enhancing the oral bioavailability of curcumin. The purpose of coating was to reduce the burst release
of curcumin from SLN in gastric acidic environment in order to avoid curcumin degradation. In vitro
release experiment suggested a negligible amount of drug release in gastric fluid from NCC coated
SLN, whereas unmodified SLN exhibit burst release. In contrast, sustained release was observed
in simulated intestinal fluid suggesting an advantage of coating to deliver most of the drug to the
intestine. Further, higher AUC and Cmax of curcumin were observed in vivo from NCC modified SLN.
These results suggested NCC modified SLN facilitate intestinal absorption by increasing lymphatic
Pharmaceutics 2018, 10, 191 12 of 21

uptake (which allows formulations to avoid CYP3A-mediated hepatic first pass metabolism), and by
decreasing 2018,
Pharmaceutics drug10,degradation in acidic environment [65].
x FOR PEER REVIEW 12 of 21
Similarly, Wang et al. developed chitosan coated cisplatin loaded SLN (CChSLN) for enhanced
CChSLN
anticancertowards
activity killing of cancer
in cervical cancer.cells compared
In vitro to uncoated
cytotoxicity particles.superior
assay suggested Higher apoptosis
activity of potential
CChSLN
of CChSLN
towards killingcompared
of cancer to uncoated
cells comparedSLN and freeparticles.
to uncoated drug could
Higherbeapoptosis
attributed to theofenhanced
potential CChSLN
internalization (due toSLN
compared to uncoated cationic charge)
and free drug and
couldcontrolled release
be attributed ofenhanced
to the drug obtained from CChSLN
internalization (due to
formulation
cationic charge)[66].and controlled release of drug obtained from CChSLN formulation [66].

11. Applications
11. Applications of
of Solid
Solid Lipid
Lipid Nanoparticles
Nanoparticles
SLNs enhance the
SLNs thebioavailability
bioavailabilityofofentrapped
entrappeddrugs
drugsviavia
modification of the
modification dissolution
of the rate,rate,
dissolution and
can be used to improve tissue distribution and targeting of drugs. Possible applications of SLNs
and can be used to improve tissue distribution and targeting of drugs. Possible applications of SLNs are
represented
are in Figure
represented 7. 7.
in Figure

Figure 7.
Figure Schematic representation
7. Schematic representation of
of applications
applications of SLNs.

11.1. Controlled Release of Drug

11.1. Controlled Release of Drug
SLNs offer an advantage to modulate release of loaded drug either by varying drug loading
SLNs offer an advantage to modulate release of loaded drug either by varying drug loading
approach or by altering surface properties or composition. In a recent study, SLN loaded with TNF-α
approach or by altering surface properties or composition. In a recent study, SLN loaded with TNF-
siRNA was developed to achieve its prolonged release in treatment of rheumatoid arthritis. SLNs
α siRNA was developed to achieve its prolonged release in treatment of rheumatoid arthritis. SLNs
were prepared via a solvent displacement method using biocompatible lecithin and cholesterol, and
were prepared via a solvent displacement method using biocompatible lecithin and cholesterol, and
a complex of siRNA with 1,2-dioleoyl-3-trimethylammonium-propane was encapsulated therein.
a complex of siRNA with 1,2-dioleoyl-3-trimethylammonium-propane was encapsulated therein. In
In vitro release study of siRNA from SLNs demonstrates absence of burst release, and only 5% of
vitro release study of siRNA from SLNs demonstrates absence of burst release, and only 5% of siRNA
siRNA was released in 30 days. This prolonged release property without burst release was attributed
was released in 30 days. This prolonged release property without burst release was attributed to the
to the presence of cholesterol and complex of siRNA in formulation [67].
presence of cholesterol and complex of siRNA in formulation [67]
Cavalli et al. prepared inclusion complexes of hydrocortisone and progesterone with cyclodextrin
Cavalli et al. prepared inclusion complexes of hydrocortisone and progesterone with
by co-precipitation method. Inclusion complexes were later incorporated into different types of
cyclodextrin by co-precipitation method. Inclusion complexes were later incorporated into different
SLNs. The authors observed a delayed release of drug from SLNs of drug-cyclodextrin complex [68].
types of SLNs. The authors observed a delayed release of drug from SLNs of drug-cyclodextrin
Achieving controlled release of hydrophilic drugs using SLNs as a carrier is usually challenging due
complex [68]. Achieving controlled release of hydrophilic drugs using SLNs as a carrier is usually
challenging due to poor drug loading. However, controlled release of a hydrophilic peptide drug,
gonadorelin, was achieved using SLN due to the ability of this carrier to load high amount of
gonadorelin (up to 69.4%) by solvent diffusion technique. Drug release behavior from this
Pharmaceutics 2018, 10, 191 13 of 21

to poor drug loading. However, controlled release of a hydrophilic peptide drug, gonadorelin, was
achieved using SLN due to the ability of this carrier to load high amount of gonadorelin (up to 69.4%)
by solvent diffusion technique. Drug release behavior from this monostearin SLNs exhibited a biphasic
pattern. After burst release (24.4% during first 6 h), a distinctly prolonged release for over 12 days was
observed [69].
Jain et al. formulated an anti-acne SLN-based hydrogel for topical delivery of adapalene for
treatment of acne [70]. Kim et al. prepared a novel formulation based on a pH-sensitive system.
In this system, curcumin loaded SLNs, which act as depot, were coated with mesoporous silica matrix,
to control the release of curcumin. A pH dependent release was observed from this complex, which
could be attributed to the interaction between silanols of the mesopore surface and curcumin [71].

11.2. SLNs for Targeted Brain Drug Delivery

SLNs can improve the ability of the drug to penetrate through the blood-brain barrier (BBB).
Abbas et al. targeted clonazepam to brain via intranasal olfactory mucosa utilizing nanolipid carriers
that were co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs), both for the guidance
of nanocarrier and holding in external magnetic field. The nanolipid carriers are incorporated in situ
in thermosensitive mucoadhesive gels, resulting in the enhanced delivery of clonazepam. This study
raises the light on new intranasal management of epilepsy with reduction in clonazepam peripheral
harmful effects [72].

11.3. SLNs for Anticancer Drug Delivery

Recently, SLNs bearing anti-neoplastic drug have been investigated for breast cancer treatment,
and results showed a sustained release of tamoxifen with good therapeutic activity [73]. Surface
modified SLNs can be fabricated for tumor targeting purposes with help of a suitable targeting ligand
for effective delivery of some anticancer drugs like methotrexate (MTX) and camptothecin [74].
Gomes et al. developed lipid core nanoparticles (LDE) containing antiproliferative agent PTX
and reported the reduction in atherosclerosis lesions induced in rabbits through cholesterol feeding.
After withdrawal of feeding of cholesterol, as compared to LDE-single group, the LDE-PTX and
LDE-PTX+LDE-MTX managements has the ability to rise by 49 and 59% plaque areas regression,
respectively. The tumor necrosis gene expression factor α was decreased by 65 and 79% using LDE-PTX
and LDE-PTX+LDE-MTX, respectively. This result showed the action of combined chemotherapy for
achieving higher effects on strongly atherosclerotic inflamed lesions [7].
Chirio et al. developed distearoyl-floxuridine loaded SLN having 70.8–82.8% entrapment ability.
In vitro cytotoxicity study performed on human cancer cell lines like HT-29, MDA-MB231 and
M14 cells suggested the superior activity of distearoyl-floxuridine SLN towards cancer cell killing.
The distearoyl floxuridine SLNs were found to be 100 times more efficient as compared to free
floxuridine. Furthermore, clonogenic assay suggested higher cytotoxicity of distearoyl-floxuridine
SLN as compared to free drug [75].

11.4. SLNs for Antimicrobial Drug Delivery

SLNs release antimicrobial payloads for the effective elimination of infectious microbes harbored
at lymphatic sites [8]. Nanoparticles and the nanostructured surfaces oppose the growth of bacteria
and infections, which is an effective solution regarding difficulties related to biofilm and antibiotic
resistance. SLNs are manufactured for delivery of antimicrobial agents and act against microbes by
encapsulating the antimicrobial drugs, disruption of microbial adherence, and receptor-based binding
to cellular surfaces [76].

11.5. SLNs as Gene Carrier

Several studies have been carried out on SLN bearing genetic materials such as plasmid
deoxyribonucleic acid (p-DNA), DNA, and other nucleic acids [7]. Vicente-Pascual et al. reported
Pharmaceutics 2018, 10, 191 14 of 21

that SLN based vectors could act as a beneficial system of gene delivery for management of corneal
diseases and inflammation [77].

11.6. SLNs for Topical Use

SLNs are used topically to deliver various drugs such as vitamin A, sisotretinoin, and flurbiprofen.
The flurbiprofen-loaded SLN gel can be applied directly to the site of action, to induce higher tissue
concentrations of the drug in controlled fashion [20].
SLN loaded diflunisal (DIF), a non-steroidal anti-inflammatory drug, has also been developed
for effective management of rheumatoid arthritis. SLNs formulated by hot homogenisation method
(based on microemulsification technique) were spherical in shape with a mean size of 124.0 ± 2.07 nm
(PDI 0.294 ± 0.15). These SLNs showed significant decrease in fluid volume, granuloma tissue weight,
leukocyte count/mm3 in mice air pouch model. Similarly, in mice ear oedema and rat paw oedema
model, 2.30 and 1.29 times increase in percentage inhibition of oedema was observed respectively,
using SLN formulation compared to conventional cream [78].

11.7. SLN in Cosmetics

SLNs are novel nanocarriers that can replace the conventional delivery systems such as creams,
gels, ointments usage in cosmetics [29,79]. Gonçalez et al. found that curcumin (CUR) have therapeutic
properties against skin disorders (SD). The cationic SLNs (CSLN) loaded with CUR were developed
and analyzed physicochemically for SD. It was suggested that the surface charge of CSLN (zeta
potential, +23.1 to +30.1 mV) played a major role in selective accumulation of drug to the diseased
tissue [80].
Jose and Netto compared lipid nano-based systems and traditional cosmetic products on account
of occlusiveness. The film formed via lipid nanoparticles on skin was smooth in comparison to film
formed using a traditional paraffin product. SLNs based products showed great activity of UV-blocking
and photoprotection [29].

11.8. SLNs as Adjuvant for Vaccines

Immunologic adjuvants are substances that are used to augment the degree, stimulation, or
robustness of vaccines. In this sequence, Stelzner et al. developed squalene containing steam sterilized
SLNs based adjuvant system for a yeast-based vaccine. Size of squalene loaded SLN measured by
static and DLS technique was found to be in the range of 120–170 nm. Evaluation of the developed
vaccine adjuvant on a mouse model showed excellent efficacy against the harmful bursal virus
disease. Squalene-based adjuvants represented high biocompatibility and also demonstrated immune
stimulation properties, which is comparable with Freund’s adjuvant [81].

11.9. SLNs in Antitubercular Chemotherapy

In the current scenario, SLNs and other nanocarriers are utilized to eradicate Mycobacterium
tuberculosis completely [82]. Castellani et al. reported that SLNs could work as efficient drug delivery
system for the natural anti-oxidants derived from seed of grape in oxidative stress model in airway
epithelial cells. The authors pointed long-term persistence and stability inside cells and liberation of
proanthocyanidins. Their results create a path for novel anti-inflammatory and anti-oxidant therapies
for chronic respiratory diseases [83].

11.10. SLNs in Bioimaging

The detection and removal of lipopolysaccharides (LPS) from pharmaceutical preparations and
food is vital for safe administration and to prevent septic shock. An abiotic system prepared using
SLNs aim at reversible capture, detection, and removal of LPS in aqueous solutions. Furthermore,
Pharmaceutics 2018, 10, 191 15 of 21

the regenerated particles also act as colorimetric labels in the dot blot bioassays for basic and prompt
evaluation of the LPS elimination [84].
In the advanced field of nanomedicine, diverse approaches for rheumatoid arthritis (RA) therapy
are available. Albuquerque et al. developed anti-CD64 antibody anchored SLN based theranostic
system consisting of SPIONs and MTX (co-encapsulated in the SLNs) for targeting the macrophages in
RA. The formulations have sizes lower than 250 nm and -16 mV zeta potential with suitable features
for intravenous administration. TEM photographs showed that SPIONs were encapsulated within
SLN matrix and obtained values of MTX association efficiency were greater than 98%. In vitro studies
demonstrated that all formulations exhibited low cytotoxicity up to 500 µg/mL concentration in THP-1
cells. The SLN based formulations are, therefore, promising candidates for both therapeutic and
imaging purposes [85].

12. Toxicity Aspects of SLNs

Materials used in drug delivery systems should be biocompatible and assessment of
biocompatibility is an obligatory viewpoint to address. While an exact assurance of the toxicity
of a formulation must be resolved through in vivo studies, an assortment of In vitro toxicological
assays, performed in satisfactorily selected cell lines, may give extremely helpful data. These tests are
broadly acknowledged as first markers of toxicity [86].

12.1. Cytotoxicity of SLNs

Assurance of cell toxicity or cell viability remains the furthermost regular test utilized as
confirmation of biocompatibility or toxicity. SLN prepared using glyceryl monostearate has been
tested for their cytotoxicity In vitro on monkey kidney epithelial cells (VERO) and acute lymphoblastic
leukemia cells (L1210) using MTT assay. The 50% inhibitory concentration (IC50 ) of SLN was found
to be 0.7 and 0.4 mg/mL in VERO cells and 0.5 and 0.3 mg/mL in L1210 cells, after 24 and 48 h of
incubation, respectively [87].
In another study SLNs prepared using Softisan® 154 and soy lecithin via high-pressure
homogenization technique were tested on MCF-7 and MDA-MB231 for their toxicity. The IC50 values
reported in this study for MCF-7 cells were found to be approximately 0.28, 0.26, 0.22 mg/mL after 24,
48 and 72 h, respectively. Similarly, IC50 values observed for MDAMB-231 cells were found to be about
0.29, 0.29, 0.27 mg/mL after 24, 48, and 72 h, respectively [88]. It can be concluded that the lipid used
to prepare nanoparticle has significant effect on the cytotoxicity of obtained SLNs.

12.1.1. Impact of Surface Charge

The interaction between the colloidal nanoparticles and cells depend on the surface charge of the
particles. Cationic surfactants used in SLNs can create deformities in membrane integrity [89] and
sensitize the immune system [90].

12.1.2. Effect of Composition on Cell Viability

Identification of the surfactants used for SLNs, not only in terms of biocompatibility but also
for the stability or shelf life, is something very important for the SLNs system. Pluronic® F-68 and
Tween 80 were used in topical, oral liquid, and semisolid dosage forms. Assessment of both surfactants
(Pluronic® F-68 and Tween 80) for cell viability incorporated in SLNs was made. Pluronic® F-68 in
SLNs has shown good stability and 90% cell viability, whereas Tween 80 in SLNs with same lipid
composition has shown better stability but with 50% cell viability [91]. The nature of surfactant used in
SLNs and duration of contact time of SLNs with cells will influences the cell viability percentage [92].
Pharmaceutics 2018, 10, 191 16 of 21

12.2. Genotoxicity
Several studies suggested that SLN does not show any damage to DNA or gene related toxicity.
Dolatabadi et al. and Bhushan et al. investigated SLN with negative charge by incubating with A549
cells, and found that these did not produce any toxicity or harm to genome DNA determined by gel
electrophoresis [92,93]. However, a report suggested damage in DNA by acetyl shikonin-bearing SLN,
which instigated an increase in comet development in A549 cells. SLN-encapsulated drug further
increased the DNA damage [94].

12.3. Hemolytic Toxicity

Hemolysis examination was usually performed to evaluate the extent of red blood cell destruction
caused by i.v. injection of foreign material [95]. Lakkadwala et al. evaluated SLNs consisting of
glycerol monostearate and polysorbate 80 for their hemotoxicity, and the obtained results demonstrated
low hemotoxicity of SLN even at high dose (1 mg/mL) [73]. Hyaluronic acid coated SLN bearing
antineoplastic drug also demonstrated low hemolytic toxicity, regardless of whether the formulation
displayed a cationic surface or an anioinic surface [96]. Another cationic SLN bearing doxorubicin was
found to be non-hemolytic. This impact was additionally articulated when SLNs were covered with
galactose [97].

13. Marketed Formulations of Solid Lipid Nanoparticles

To enhance the bioavailability of BCS class II drugs, lipid-based formulations have been utilized.
Around 4% of commercially available products in the United States, United Kingdom, and Japan
market are oral lipid based formulations. Oral lipid based systems vary from simple lipid solutions to
self-emulsifying drug delivery systems (SEDDS) [98].

14. Conclusions and Future Perspectives

SLNs are an amalgamation of the properties of liposomes and polymer based carriers, where
encapsulation of both lipid soluble and water soluble drugs could be possible. Production of SLN is
inexpensive, and scale up is feasible. They pose high stability during their shelf life, and a wide range
of lipids are available for tuning the release kinetics. SLNs have emerged as efficient drug delivery
systems and the future of lipid based drug delivery is largely dependent on SLNs due to their various
significant properties. Scientists have already filed many patents related to SLNs and we can anticipate
more patented SLN-based delivery systems in the near future.

Funding: This study was funded by Academy of Finland grant numbers 309374 and 309794.
Conflicts of Interest: The authors declare no conflicts of interest.

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