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TUGAS JURNAL
Pharm Tech
Sistem Pelarut Oro Dari Ekstrak Pepaya – Liquisolida Padat Dan Tablet Hisap
Abstrak: Tujuan: Mengembangkan oro oro- pelarutan sistem carica papaya ekstrak daundengan
berbagai teknik untuk meningkatkan efek terapeutiknya.
Metode:segar pepaya Ekstrak daundibuat dengan metode ekstraksi dingin dan maserasi. Itu
komponen ekstrak dianalisis dengan teknik GC GC-MS.
MS. Ekstrak pekat diformulasikan lebih lanjut
menjadi butiran liquisolid dan tablet hisap lunak dengan me metode
tode pemadatan dan pencetakan
liquisolid. Berbagai uji kendali mutu seperti variasi berat, kekerasan, ketebalan dan diameter
serta disintegrasi dilakukan untuk mengevaluasi kelayakan komersial formulasi. Analisis XRF
dan beban mikroba adalah dilakukan uuntukntuk set tablet dan tablet hisap yang dioptimalkan dan
hasil dihitung.
Hasil: Kedua formulasi menunjukkan hasil 80% dan sifat aliran yang dapat diterima memenuhi
kebutuhan standar kualitas. GC
GC-MSMS melaporkan adanya 12 senyawa utama dengan spektrum
yang serupa. Itu Hasil XRF menunjukkan adanya jumlah tinggi kalium (K) dan jumlah jejak
tembaga dan molibdenum. Tes batas mikroba menunjukkan jumlah total aerobik dan jamur
dalam batas sesuai farmakope India.
Kesimpulan: Formulasi ditemukan stabil dan dalam batas farmakope standar, memuaskan
kondisi untuk pelepasan dan kerja obat aktif yang efektif.
Kata kunci: Carica papaya,, oro
oro-solving, liquisolid, soft lozenge.
Pendahuluan:
Obat-obatan herbal adalah biji tanaman, kulit kayu atau bunga yang digunakan untuk
tujuan pengobatan yang telah teruji oleh waktu untuk keamanan, kemanjuran, penerimaan
budaya dan efek samping yang lebih kecil. Unsur kimiawi yang ada terlibat dalam fungsi
fisiologis tumbuhan hidup yang berkontribusi pada kompatibilitas yang lebih baik dalam sistem
biologis. Carica papaya L. adalah pohon abadi bertangkai tunggal kayu lunak yang termasuk
dalam keluarga Caricaceae (1). Kulit daun tanaman menghasilkan senyawa alami yang memiliki
sifat anti tumor dan pestisida (2). Belakangan ini daun pepaya menunjukkan adanya banyak
komponen aktif seperti papain, chymopapain, glukosinolat, tokoferol, asam askorbat, flavonoid,
glukosida sianogenik dan sistatin yang bertanggung jawab untuk meningkatkan daya antioksidan
total dalam darah dan mengurangi peroksidasi lipid. tingkat 3). Daun muda memiliki aktivitas
antibakteri dan dapat digunakan untuk pengobatan penyakit kuning (pasta halus), keluhan
kencing, kencing nanah (infus) dan pembalut luka (daun segar). Ikan mas, alkaloid dengan rasa
pahit yang intens memiliki efek depresan yang kuat pada jantung diperoleh terutama dari daun
pepaya (4).
Ekstrak daun bertindak sebagai agen perusak tumor yang kuat yang terdiri dari berbagai
fitokonstituen seperti glikosida jantung, tanin, saponin dan alkaloid (seperti karpain,
pseudokarpain dan dehidrokarpain I dan II) yang mencegah kerusakan sumsum tulang sehingga
meningkatkan kemampuannya untuk menghasilkan trombosit. Lebih lanjut, mereka dapat
meningkatkan kehidupan platelet dalam sirkulasi dengan mencegah kerusakan platelet dalam
darah (5,6). Teknik pemadatan liquisolid diterapkan untuk konversi massa yang mengalir bebas
menjadi bentuk sediaan unit tunggal yang dipadatkan yang meningkatkan laju pelarutan obat,
dalamtidak mudah menguap.
Prosesnya melibatkan pencampuran sederhana obat cair atau campuran dengan eksipien
seperti pembawa seperti selulosa mikrokristalin dan bahan pelapis seperti silika koloid yang
menghasilkan pembentukan massa lembab dari bubuk yang tampaknya kering dan mudah
dikompresi. Konsentrasi pembawa, bahan pelapis, disintegran, pelumas dan glidan
mempengaruhi campuran yang tidak lengket dan mudah dikompres, yang dapat langsung
dikompresi. Teknik liquisolid yang dimodifikasi saat ini melibatkan pemadatan ekstrak herbal
menjadi massa bubuk yang memfasilitasi dalam meningkatkan kelarutan / disolusi dan stabilitas
bahan aktif.
Lozenges adalah bentuk sediaan padat yang larut perlahan di mulut yang mengandung
bahan aktif bersama dengan agen pemanis untuk meningkatkan rasa, memastikan bahwa obat
tersebut bersentuhan dengan jaringan mulut untuk jangka waktu tertentu yang pada gilirannya
meningkatkan penyerapan (7). Tablet hisap lembut memiliki tekstur yang halus yang biasanya
terbuat dari bahan-bahan seperti polietilen glikol (PEG), coklat, atau dasar gula akasia. Tablet
hisap ini dapat digulung dengan tangan dan kemudian dipotong-potong yang berisi jumlah aktif
yang dibutuhkan bahan atau mereka dapat dibuat dengan menuangkan massa hangat ke dalam
cetakan troche plastik juga (8). Liquisolid compacts dan lozenge adalah sistem pelarutan oro
yang dimaksudkan untuk penyerapan yang lebih cepat dan lengkap. Tujuan Penelitian ini
merancang sistem pelarutan oro menggunakan ekstrak Carica papaya untuk meningkatkan terapi
efek.
Bahan dan Metode
Daun pepaya Carica hijau dikumpulkan dari Thirumalaisamudiram (Thanjavur). Mannitol,
Lactose Monohydrate, Cellulose Micro Crystalline, Magnesium Stearate, Talc, PEG 4000, PEG
600, dan Acacia dibeli dari SD Fine Chemicals Ltd, Mumbai, India. Semua reagen buffer adalah
kelas analitik.
Ekstraksi dingin
Daun Carica pepaya hijau yang telah dikumpulkan dicuci dengan aquades dimana 50 gram daunnya
dihaluskan dan dihaluskan dalam blender dengan menggunakan akuades 200 ml untuk mendapatkan sari
dari daun segar (9).
Maserasi
Ekstrak air Carica Papaya dibuat dengan air suling 100% dengan menambahkan 50 g daun
potong segar ke dalam 200 ml air suling. Campuran disimpan dalam suhu kamar selama dua
hari. Pada akhir hari pertama air yang mengandung ekstrak disaring dan dikumpulkan, kemudian
disuspensikan kembali dengan akuades segar 200ml dan dilanjutkan maserasi keesokan harinya.
Akhirnya kedua ekstrak digabungkan.
Konsentrasi Ekstrak
Campuran dipanaskan pada suhu 50-60˚ C selama 48 jam. Prosedur ini melibatkan proses decoction
sederhana dari ekstrak encer dimana senyawa terlarut dipanaskan lebih lanjut pada suhu yang lebih tinggi
yaitu 70-75˚C selama 3 jam sampai pelarut benar-benar menguap. Temperatur dijaga untuk menghindari
produk menjadi hangus. Produk kering yang diperoleh ditimbang dan dicatat hasilnya (10,11).
Mannitol 4,25 4
Selulosa 4,25 4
Berat total
Magnesium Stearat 17,75 15
1,99% -
Bedak 1,99% -
Ekstrak pekat Carica papaya dicampur dengan eksipien seperti mikrokristalin selulosa,
laktosa monohidrat dan manitol (rasio 1: 1: 1) untuk meningkatkan bulkinessnya dan diubah
menjadi massa bubuk dengan sifat aliran yang dapat dilalui dan kompresibilitas. Itu dilewatkan
melalui saringan no: 25 untuk memecahkan gumpalan untuk mendapatkan butiran seragam yang
akhirnya ditambahkan bedak dan magnesium stearat
stearat.. Berat total butiran dicatat (12, 13). (Tabel
1).
Formulasi Butiran (14, 15)
Evaluasi Pra-Formulasi
Sudut diam
Properti aliran butiran dinilai dengan metode corong. Butiran yang ditimbang dilewatkan
melalui corong yang ditempatkan pada ketinggian 5 cm dari alasnya. The tinggi dan diameter
tiang tercatat dari mana sudut istirahat dihitung dengan menggunakan rumus,
θ = tan ˉ 1(h / r)
Dimana, θ = Sudut Repose
h = tinggi Pile
r = Radius tumpukan
Kepadatan Massal
yang butiran ditimbang secara akurat dan ketinggiannya diukur dalam gelas ukur 100 ml
setelah diratakan dari mana volume tidak stabil (Vo) dicatat.dihitung sebagai,
Kerapatan keran
Butiran yang ditimbang secara akurat dipindahkan ke silinder ukur dari mana kerapatan
keran ditentukan dengan mengetuk silinder pengukur yang berisi butiran yang telah ditimbang
sebelumnya (M) secara perlahan di atas bidang kayu dari 1 inci ( h) di atas, dengan interval
reguler 2 detik selama 500 kali. Densitas tap adalah rasio berat sampel terhadap volume tap.
Indeks Carr
Indeks Carr juga disebut sebagai indeks kompresibilitas, adalah ekspresi porositas butiran
yang merupakan indikasi sederhana untuk aliran material yang baik. Berdasarkan densitas bulk
semu dan densitas tap, persentase kompresibilitas obat curah ditentukan dengan rumus.
rumus
Preparasi Tablet
Granul liquisolid dipadatkan menjadi tablet dengan metode kompresi langsung dengan bobot
rata-rata seragam menggunakann mesin tablet berlubang tunggal (Khera). Instrumen, New Delhi).
Mesin tersebut disesuaikan untuk mendapatkan ukuran dan berat yang diinginkan (16, 17).
Evaluasi Tablet Liquisolid (18, 19, 20)
Uji Variasi Berat Uji variasi
Bobot dilakukan terhadap 20 tablet secara acak dengan menimbang masing
masing--masing tablet
secara individual dan dihitung bobot rata
rata-ratanya.
Friabilitas
10 tablet ditimbang dan ditempatkan dalam peralatan uji friabilator Roche yang kemudian
digulung untuk kejutan berulang, akibat jatuh bebas di dalam peralatan. Setelah 100 putaran
tablet dihilangkan debu dan ditimbang lagi. Tablet yang kehilangan berat kurang dari 1%
dianggap patuh. Kerapuhan ditentukan dari ekspresi,
Kekerasan
Kekerasan tablet ditentukan dengan menggunakan tester kekerasan Monsanto. Tablet yang
akan diuji ditempatkan di antara spindel dan landasan, dan tekanan yang diinginkan diperlukan
untuk menahan tablet pada posisinya diikuti dengan menggerakkan kenop sekrup searah jarum
jam sampai tablet rusak. Pembacaan dicatat, yang menunjukkan tekanan yang diperlukan
di untuk
2
memecahkan tablet yang ditunjukkan dalam Kg / cm .
Waktu disintegrasi
Waktu hancur enam tablet dihitung dengan menggunakan alat uji disintegrasi (Lab India
DT100). Setiap tablet dimasukkan ke dalam tabung rakitan rak keranjang dari peralatan
disintegrasi tanpa cakram. Rakitan ditempatkan dalam gelas kimia yang beri
berisi
si media disintegrasi
(air) yang dipertahankan pada suhu 37 ± 2 ° C dan waktu yang diperlukan untuk disintegrasi
lengkap dicatat sebagai waktu hancur.
Prosedur Pembuatan Permen Lembut Tablet
Hisap lunak dibuat dari PEG 600 dan 4000 dengan perband
perbandingan
ingan 1: 1 (masing-masing
(masing 10 g),
dengan dasar getah akasia (0,5 g) yang memberikan tekstur dan kehalusan pada permen pelega
tenggorokan. Prosedur formulasi membutuhkan proses pemanasan sekitar 50 50˚C
˚C (21, 22). PEG
dilebur dalam bak air yang ditambahkan akasi
akasiaa dan diaduk rata. Kemudian ekstrak mentah
segera dituangkan ke dalam cetakan dan kemudian didinginkan, yang ditempatkan dalam freezer
untuk pemadatan lengkap dan kemudian tablet hisap dikeluarkan dari dalamnya.
Evaluasi tablet hisap
Berat rata-rata 20 tablet hisap yang dibuat dengan teknik ekstraksi dingin dan maserasi
dihitung. Ketebalan, diameter dan waktu hancur diukur dengan prosedur yang mirip dengan yang
dilakukan pada tablet. Hasilnya ditabulasikan.
Protokol Gcms
Untuk menemukan komponen individu yang ada dalam ekstrak air daun pepaya Carica,
sistem GC Clarus 500 Perkin Elmer dihubungkan ke Spektrometer Massa. Kondisi yang
digunakan adalah, Kolom: Elite 5 MS (5% fenil 95% dimetil polisiloksan), Dimensi: 30 х 250
µm, Gas pembawa: Helium, Laju aliran konstan 1ml / menit, Volume injeksi: 10µl, Suhu
injektor: 270° C, Suhu sumber ion: 200° C, Pemrograman oven: 50° C pada 8 ° C / menit hingga
200 ° C selama 5 menit dan hingga 280 ° C selama 10 menit dan rentang MS: 40-600 amu
menggunakan ionisasi elektron. Juga kondisi suhu untuk jalur transfer dan sumber masing-
masing adalah 200 ° C dan 180 ° C. Data yang diperoleh berkorelasi dengan data yang ada di
NIST (National Institute of Standards and Technology).
Analisis
XRF Studi XRF dilakukan untuk tablet yang dioptimalkan untuk memperkirakan
persentase konsentrasi ion logam dalam formulasi. Analisis unsur dilakukan untuk komponen-
komponen seperti kalsium, besi, silika, titanium, natrium, timbal, nikel, magnesium, dll. Cawan
aluminium diisi dengan asam borat dan kemudian 1 gram sampel tablet digunakan untuk
menutupi asam borat secara halus. Aluminium cup dipelletkan menggunakan hydraulic press
pada 25 ton untuk mendapatkan pellet berdiameter 34 mm. Sampel dianalisis dalam kondisi
vakum dalam mode oksida menggunakan spektrometer XRF (Model: Bruker S8 Tiger) yang
dilengkapi dengan tabung sinar-X anoda Rh 4 KW. Konsentrasi unsur dinyatakan dalam ppm.
Persentase hasil ditemukan lebih besar dari 80% untuk kedua butiran yang dibuat dengan
metode maserasi dan ekstraksi dingin daun Carica papaya, Sifat aliran bubuk dan ketahanan
gerakan partikel terhadap partikel dapat dinilai dengan menggunakan sudut diam. Sudut istirahat
lebih besar dari 25%, menunjukkan sifat aliran yang dapat diterima. Indeks kompresibilitas
berada pada kisaran 36% untuk kedua butiran yang dibuat dengan menggunakan metode
ekstraksi yang berbeda. Juga campuran yang disiapkan menunjukkan sifat kompatibilitas yang
baik. Semua tablet disiapkan dalam kondisi yang sama dan ditemukan memenuhi kualitas
standar yang disyaratkan. Nilai pra-parameterkompresi yang dievaluasi ternyata berada dalam
batas yang ditentukan, yang menunjukkan kesesuaian untuk proses kompresi (15).
Evaluasi Tablet
Sesuai dengan batas farmakope, deviasi 7,5% diperbolehkan untuk sekitar 300 mg butiran
padat dengan berat rata-rata. Berat tablet berada dalam kisaran 274,45 sampai 318,95 mg.
Compacts, siap dengan ekstrak maserasi ditemukan untuk menunjukkan kekerasan seragam 2 Kg
/ cm2 sedangkan metode ekstraksi dingin menunjukkan kekerasan rata-rata 2,16 Kg / cm2,yang
menunjukkan kekuatan mekanik yang baik. Diameter dan ketebalan ditemukan masing-masing
8,6 mm dan 4,9-5,5 mm. Pada semua formulasi nilai kerapuhan kurang dari 0,25% yang
menunjukkan bahwa tablet yang diformulasikan stabil secara mekanis. Variasi persentase bobot
masih dalam batas. Waktu hancur kurang dari 15 menit untuk formulasi yang berbeda (15, 19)
(Tabel 3)
Tabel 3: Evaluasi tablet
Berat rata-rata, ketebalan, diameter dan waktu hancur dihitung untuk tablet hisap lunak
yang dibuat dengan metode ekstraksi dingin dan maserasi, dan hasil yang diperoleh
ditabulasikan. (Tabel 4) Karena cetakan yang digunakan untuk maserasi dan ekstraksi dingin
sama, maka perbedaan diameter dan ketebalannya dapat diabaikan.Berat rata-rata lebih banyak
pada tablet yang dibuat dengan ekstraksi dingin (818,05mg) daripada maserasi (770,33 mg),
karena dengan kepadatan ekstrak dingin yang tinggi jika dibandingkan dengan ekstrak yang
dibuat dengan maserasi. Alasan yang sama dapat dikaitkan dengan waktu hancur yang lebih lama
pada yang pertama (3-4 menit) dibandingkan dengan yang terakhir (1,05 menit).
C H O
2. Diglycerol 6 14 5 166 2,1357 10,65 3.996.790
C H
3. 2-Pyrrolidinone 4 7NO 85 12,9651 11,82 24.262.978
C H
4. 7-Hexadecene, (Z) - 16 32 224 0,2368 16,66 443.203
C H
5. 6,11-Dimethyl-2,6 , 10- 14 24O 208 0,0188 17,83 35.176
dodecatrien-1-ol
C H
6. Fenol, 2,4-bis (1,1- 14 22O 206 0,9331 19,01 1.746.271
dimethylethyl) -
C H
7. 3-Octadecene, ( E) - 18 36 252 0,5217 19,84 976310ftala
t
C H O
8. Asam, etil pentil 15 20 4 264 0,1445 20,20 270421
ester
C H
9. 2 (1H) - 5 5NOS 127 0,1118 20,35 209273
Piridinetion, 3-
hidroksi
C H
10 3-Eicosene, (E) - 20 40 280 0,3072 23.10 574.842
.
C H
11 2-Hexadecene, 1,380
20 280 23,88 40
3,7,11,15- 9258418
tetramethyl-, [R [R 4
*, R * - (E)]] -
C H
12 3,7,11,15- 20 40O 24,708 24,05
.. Tetramethyl-2- 046238
hexadecen-1-ol 7443,7,
11,15-
Tetram
ethyl-2
C H
13 296 - 20 40O 296 3,8675 24,6 4 7237650
.
hexadecen-1-ol
C H
14 4,8,12- 17 30O 250 0,2103 26,20 393501
. Tetradecatrien-1-ol,
5,9,13-trimethyl
C H
15 5-Hexen-3-ol, 2,2, 4- 9 18O 142 0,1614 26,44 302.124
. trimetil
C H
16 3-Undecene, (E) - 11 22 154 0,9397 27,43 1.758.534
.
C H O
17 n-hexadecanoic asam 16 32 2 256 16,7326 27,89 31.313.546
.
C H
18 1- Hexadecanol 16 34O 242 0,4681 30,21 875.978
.
C H
19 3-Eicosene, (E) - 20 40 280 0,4083 30,55 764.042
.
C H
20 fitol 20 40O 296 1,8689 30,65 3.497.463
.
C H
21 cis, cis, cis-7, 10,13- 16 26O 234 29,0445 31,68 54354232
. Hexadecatrienal
C H
22 Isomer Farnesol a 15 26O 222 0,3991 34,86 746857
.
C H
23 1,3- 10 17N 151 1,4115 36,42 2.641.488
. Cyclopentadiene, 5-
[3- (dimethylamino)
propyl] -
C H
2424. Y All-trans-Squalene 30 50 410 0,2571 43,41 481.199
Analisis XRF
Dari hasil XRF dari Carica ekstrak daun pepaya tablet, diamati bahwa, unsur kalium (K)
hadir di tinggi jumlah sekitar 54,65%, diikuti oleh Magnesium (Mg) 12,10%, unsur tembaga dan
molibdenum yang dikirim dalam jumlah sedikit di kisaran 0,08%. Dalam hal senyawa oksida,
silikon-di oksida ditemukan dalam persentase tinggi sekitar 25,21% diikuti oleh Kalium oksida
(K2O - 21,46%) dan Tembaga (II) oksida yang memiliki senyawa oksida paling sedikit yaitu
0,11% (Tabel 6). Dari penelitian sebelumnya, ditemukan bahwa natrium terdapat dalam jumlah
paling banyak diikuti oleh kalium, sedangkan fosfor ditemukan dalam jumlah paling sedikit. Di
antara unsur-unsur mikro, Besi ditemukan dalam jumlah tertinggi sedangkan Boron ditemukan
paling sedikit (24).
S 2.42 Cl 4.36
Dari hasil uji batas mikroba didapatkan bahwa jumlah total aerobik yang layak dan jumlah
total jamur berada dalam batas sesuai dengan standar Farmakope India. Ketiga mikroorganisme
seperti E. Coli, Salmonella dan Shigella tidak terdapat dalam ekstrak sehingga terbukti bahwa
ramuan herbal aman diberikan secara oral. (Tabel 7) Juga stabilitas formulasi dan sterilitas
kondisi pemrosesan diidentifikasi memuaskan.
x 2 24,06,
14-Desember-2013 + 14:26:02
GC 3028 ekstrak etanol 14 12 13 Pindai EI + TIC
31,68
100
9.29e8
68
79
27,89
43
25,12
57
11,81%
30,65
69
58
71
19,84
19,01 70
16,66
27,60
44
191
44
149
0
Time10.90 15,90 20,90 25,90 30,90 35,90 40,90
Kesimpulan
Penelitian ini melibatkan formulasi ekstrak daun segar Carica papaya menjadi kompaksi
cair-padat dan formulasi permen lunak dengan metode maserasi dan ekstraksi dingin. Parameter
pra kompresi dan pasca kompresi dari tablet ditemukan diinginkan. Hasil keseragaman dalam
bobot, uji kekerasan dan uji kerapuhan menunjukkan kecakapannya untuk pengemasan,
pengangkutan dan pemasaran yang efektif. Waktu hancur dalam batas standar memastikan
pelepasan sempurna dari komponen aktif in-vivo. Studi peningkatan skala dapat dilakukan untuk
aplikasi pada skala industri.
Pengakuan
Penulis berterima kasih kepada Universitas SASTRA yang telah menyediakan
infrastruktur dengan fasilitas laboratorium dan sumber literatur yang dibutuhkan dan juga
dorongan terus menerus untuk berhasil menyelesaikan pekerjaan.
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16. Jivraj I, Martini L, Thomson C, Gambaran tentang eksipien berbeda yang berguna untuk
langsung kompresi tablet, Pharm Sci Technolo Today, 2000, 3, 58-63.
17. Rowe RC, Sheskey PJ, Owen SC, Buku Pegangan kecuali farmasi edisi kelima, 2006. 18.
Farmakope India, Pemerintah. dari India. Kementerian Kesehatan dan Kesejahteraan Keluarga,
orang India Komisi farmakope, Ghaziabad, 2010, 1815-1817.
19. Dan, Shubhasis TKP, tablet matriks pelepasan berkelanjutan dari diltiazem hidroklorida:
formulasi pengembangan, evaluasi in-vitro dan optimasi statistik dengan metodologi
permukaan respon (RSM ), 2013, 01, 6–22.
20. Bhan S, Rathore S, Sharma A, Garg A, Sisodiya DS, Formulasi dan evaluasi salut enterik
tablet Ilaprazole, 2013, 2, 126–130.
21. Davis H. Secundum artem, Pharm J, 1948, 106, 233. Tersedia di:
http://www.ncbi.nlm.nih.gov/pubmed/15369440.
22. Laboratorium Farmasetika dan Peracikan. Tersedia di:
http://pharmlabs.unc.edu/labs/lozenge/objectives.htm.
23. Afzan A, Abdullah NR, Halim SZ, Studi dosis berulang 28 hari toksisitas oral daun Carica
papaya L. ekstrak pada tikus Sprague Dawley, Molecules, 2012, 17, 4326–4342.
24. Hardisson A, Rubio C, Baez A, Martin MM, Alvarez R, Komposisi mineral pepaya (Carica
varietas pepaya matahari terbit) dari pulau Tenerife, Eur Food Res Technol, 2001, 212, 175–
181.
.
International Journal of PharmTech Research CODEN (USA): IJPRIF
ISSN : 0974
0974-4304 Vol.6, No.7, pp 2083-2091,
2091, November 2014
Oro-Dissolving
Dissolving Systems of Papaya Extract – Liquisolid Compacts and Lozenges
Corres.author : ramya@scbt.sastra.edu
Introduction: Herbal medicines are plant’s seeds, bark or flowers used for medicinal purposes
which havee stood the test of time for their safety, efficacy, cultural acceptability and lesser side
effects. The chemical constituents present involves in the physiological functions of living flora
which contributes to better compatibility in the biological syste
system.
m. Carica papaya L. is a soft
wooded single-stemmed
stemmed perennial tree which belongs to the family Caricaceae (1). The leaf
barks of the plant produces natural compounds possessing anti-tumour and pesticidal properties
(2). In the recent times the leaves of papaya showed the presence of many active components
such as papain, chymopapain, glucosinolates, tocopherol, ascorbic acid, flavonoids, cyanogenic
glucosides and cystatin which is responsible to increase the total antioxidant power in blood and
reduction in lipid peroxidation level (3). The young leaves possess antibacterial activity and can
be used in the treatment of jaundice (fine paste), urinary complaints, gonorrhoea (infusion) and
dressing wounds (fresh leaves). Carpine, an alkaloid with an intensively bitter taste has strong
depressant action on the heart was obtained especially from papaya leaves (4).
The leaf extract acts as a potent tumour-destroying agent which consists of various
phytoconstituents such as cardiac glycosides, tannins, saponins and alkaloids (such as carpaine,
pseudocarpaine and dehydrocarpaine I and II) that prevents the destruction of the bone marrow
thereby increasing its ability to produce platelets. Further, they can increase the life of platelet in
circulation by preventing platelet destruction in the blood (5,6). The liquisolid compaction
technique is applied for the conversion of free flowing mass into a compacted, single unit dosage
form which enhances the rate of dissolution of drugs, in suitable non-volatile
D. Ramyadevi et al /Int.J yang. PharmTech Res. 2014,6 (7), hlm 2083-2091. 2084
The process involves simple blending of the liquid drug or mixture with excipients like
carriers such as microcrystalline cellulose and coating material like colloidal silica which results
in the formation of damp mass of apparently dry, readily compressible powder. The
concentrations of the carriers, coating materials, disintegrants, lubricants and glidants influence
on the non-sticky, easily compressible blend, which can be directly compressed. The present
modified liquisolid technique involves the compaction of the herbal extract into a powder mass
that facilitates in enhancing the solubility/dissolution and stability of the active ingredients.
Lozenges are solid dosage forms that dissolve slowly in the mouth which contains the
active ingredient along with sweetening agents to enhance their taste ensuring that the
medication is in contact with the mouth tissues for a certain period of time which in turn
enhances absorption(7). Soft lozenges have a smooth texture which is typically made of
ingredients such as polyethylene glycol (PEG), chocolate, or a sugar-acacia base. These lozenges
can be hand rolled and then cut into pieces which contain the required amount of active
ingredient or they can be made by pouring the warm mass into a plastic troche mold as well(8).
The liquisolid compacts as well as lozenges are oro-dissolving systems intended for faster and
complete absorption. The aim of the study is to design the oro-dissolving system using Carica
papaya extract for enhancing its therapeutic effects.
Green Carica papaya leaves were collected from Thirumalaisamudiram (Thanjavur). Mannitol,
Lactose Monohydrate, Cellulose Micro Crystalline, Magnesium Stearate, Talc, PEG 4000, PEG
600, and Acacia was purchased from SD Fine chemicals Ltd, Mumbai, India. All buffer reagents
were of analytical grade.
Preparation of Extracts
Cold extraction
The collected green Carica papaya leaves were washed with distilled water from which 50
grams of the leaves were crushed and grounded in a blender using 200 ml of distilled water in
order to obtain the juice from the fresh leaves (9).
Maceration
An aqueous extract of Carica Papaya was prepared with 100% distilled water by adding 50g
of fresh cut leaves in to 200 ml of distilled water. The mixture was kept in the room temperature
for two days. At the end of the first day the water containing the extract was filtered and
collected, then it was resuspended with 200ml fresh distilled water and the maceration was
continued again for the next day. Finally both extracts were combined.
Concentration of Extract
The mixture was heated at 50-60˚ C for 48 hours. The procedure involves simple decoction
process of the aqueous extract from which the soluble compounds further heated at a higher
temperature of 70-75˚C for 3 hours until the solvent gets evaporated completely. Temperature
was maintained to avoid the charring of the product. The obtained dry product was weighed and
the yield was noted (10,11).
Mannitol 4,25 4
cellulose 4,25 4
1,99% -
Magnesium Stearae
Bedak 1,99% -
D. Ramyadevi dkk /Int.J. PharmTech Res. 2014,6 (7), hlm 2083-2091.
2091. 2085
The concentrated extract of Carica papaya was mixed with the excipients such as
microcrystalline cellulose, lactose monohydrate and mannitol (1:1:1 ratio) in order to increase its
bulkiness and to convert in to a powder mass with passable flow property and compressibility. It
was passed through sieve no: 25 in order to break the lumps to get uniform granules in which talc
and magnesium stearate were added finally. The total weight of the granules was noted (12, 13).
13)
(Table 1)
Pre-Formulation
Formulation Evaluation of Granules (14, 15)
Angle of repose
The flow property of the granules was noted from which the angle of repose was calculated
using the formula,was assessed by funnel method. The weighed granules were passed through a
funnel which was placed at a height of 5cm from the base. The height and diameter of the pile.
pile
θ = tan ˉ 1 (h/r)
h = Pile height
r = Radius of pile
Bulk density
The granules were accurately weighed and the height was measured in a 100 ml graduated
cylinder after it was levelled from which the unsettled volume (Vo) was noted. The bulk density
was calculated as,
Tapped density
The accurately weighed granules was transferred to a graduated cylinder from which the
tapped density was determined by tapping the measuring cylinder containing pre-weighed
pre
granules (M) gently on a wooden plane from 1 inch (h) above, at regular intervals of 2 s for 500
times. Tapped density is the ratio of weight of sample to tapped volume.
Where, M = Weight of granules; Vt = Tapped volume of granules in cm3
Carr’s index
Carr’s index also called as compressibility index, is an expression for porosity of the granules
which is a simple indication for good flow of a material. Based on the apparent bulk density and
the tapped density, the percentage compressibility of the bulk drug was determined using the
formula,
Preparation of Tablets
The liquisolid granules were compacted as tablets by direct compression method with
uniform average weight using the single punch tablet machine (Khera Instruments, New Delhi).
The machine was adjusted accordingly to get the desired size and weight (16, 17).
The weight variation test was carried out for 20 tablets randomly by weighing each tablet
individually
ly and their average weight was calculated.
The thickness and diameter of the five tables was determined by using Vernier calipers.
Friability
10 tablets were weighed and placed in the Roche friabilator test apparatus which is then
subjected to rolling for repeated shocks, resulting from free falls within the apparatus. After 100
revolutions the tablets were de-dusted
dusted and weighte
weighted d again. The tablets that loose less than 1%
weight were considered to be compliant. The friability was determined from the expression,
Hardness
Hardness of the tablets was determined using Monsanto hardness tester. The tablet to be
tested was placed between the spindle and anvil, and a desired pressure was needed to hold the
tablet in position followed by moving the screw knob in clockwise directi
direction
on untill the tablet was
broken. The reading was noted, that indicates the pressure needed to break the tablet which was
indicated in Kg/cm2 .
Disintegration time
Disintegration time of six tablets was calculated using disintegration test apparatus (Lab
India DT100). Each tablet was subjected into the tube of the basket rack assembly of the
disintegration apparatus without disc. The assembly was positioned in the beaker containing
disintegration media (water) maintained at 37±2°C and the time required for complete
disintegration, was recorded as disintegrationn time.
Soft lozenges were prepared from PEG 600 and 4000 in the ratio of 1:1 (10 g each), with
gum acacia base (0.5g) which provided texture and smoothness to the lozenge. The formulation
procedure required heating process of about 50˚C (21, 22). The PEG was melted in a water bath
to which acacia was added and mixed well. Then the raw extract was immediately poured into
moulds and then cooled, which was placed in freezer for complete solidification and then the
lozenges were removed from it.
Evaluation of Lozenges
The average weight of 20 lozenges prepared by both cold extraction and maceration
techniques were calculated. The thickness, diameter and the disintegration time were measured
in a procedure similar to that performed for tablets. The results were tabulated
Gcms Protocol
In order to find the individual components present in the aqueous extract of Carica papaya
leaves, GC Clarus 500 Perkin Elmer system was interfaced to a Mass Spectrometer. The
conditions employed were, Column: Elite 5 MS (5% phenyl 95% dimethyl polysiloxane),
Dimensions: 30 х 250 µm, Carrier gas: Helium, Constant flow rate of 1ml/min, Injection
volume: 10µl, Injector temperature: 270°C, Ion-source temperature : 200°C, Oven programming:
50°C at 8°C / min to 200°C for 5 min and to 280°C for 10 min and MS range: 40 – 600 amu
using electron ionisation. Also the temperature conditions for transfer line and source were
200°C and 180°C, respectively. The data obtained was correlated with the existing data in NIST
(National Institute of Standards and Technology).
XRF Analysis
XRF study was performed for the optimized tablet to estimate the percentage of metal ion
concentration in the formulation. The elemental analysis was done for components such as
calcium, iron, silica, titanium, sodium, lead, nickel, magnesium, etc. Aluminium cups were filled
with boric acid and then 1 gram of tablet sample was used to finely cover the boric acid. The
aluminium cups were pelletized using a hydraulic press at 25 tons to obtain 34 mm diameter
pellets. The sample was analyzed under vacuum conditions in oxide mode using XRF
spectrometer (Model: Bruker S8 Tiger) equipped with a 4 KW, Rh anode X-ray tube. The
concentration of the elements was expressed in ppm.
D. Ramyadevi dkk /Int.J. PharmTech Res. 2014,6 (7), hlm 2083-2091. 2087
Microbial Load
The microbial load was estimated for the selected batch of tablets to determine its sterility
and stability. The formulations were checked for the presence of colonies due to the presence of
microorganisms such as E.Coli, Salmonella species, Shigella species and Streptococci. 1gm of
powdered tablet sample was taken and added to 9 ml of sterile distilled water for preparing the
serial dilution. The samples in the flask were kept in a mechanical shaker for few minutes to
obtain the uniform suspension. 1 ml of the 10-1 dilution solution was transferred to 9 ml of
sterile distilled water. This dilution was 1: 100 or 10-2 . This procedure was repeated up to 10-7
dilution. 0.1 ml of serially diluted samples was inoculated into the sterile plate containing
Nutrient agar, Salmonella Shigella Agar (SSA) and Potato Dextrose Agar (PDA) medium by
spread plate method. Nutrient agar and SSA plates were incubated at 37ºC for 24 hours and PDA
plates were incubated at room temperature for 3-5 days. Bacterial and fungal colonies were
counted using colony counter and checked for its standard limits
The percentage yield was found to be greater than 80% for both granules which was prepared
using maceration method and cold extraction of Carica papaya leaves, respectively.Flow
properties of the powder and resistance of particle to particle movement can be judged by using
angle of repose. The angle of repose was greater than 25%, indicating acceptable flow properties.
The compressibility index falls in the range of 36% for both granules prepared using different
extraction methods. Also the prepared blends showed good compatibility properties. All the
tablets were prepared under similar conditions and were found to satisfy the required standard
qualities. The values of pre‐compressional parameters evaluated were found to be within
prescribed limits, indicating the suitability for compression process (15).
Evaluation of Tablets
As per pharmacopoeial limits, a deviation of 7.5 % is allowed for approximately 300 mg average
weight compact granules. The weight of the tablets was within the range of 274.45 to 318.95 mg.
The compacts, prepared with maceration extracts were found to show uniform hardness of 2 Kg/
cm2 whereas the cold extraction method showed an average hardness of 2.16 Kg/ cm2 ,
indicating good mechanical strength. Diameter and thickness were found to be 8.6 mm and 4.9-
5.5 mm, respectively. In all the formulations the friability value was less than 0.25% giving an
indication that the tablets formulated were mechanically stable. The percentage weight variation
was within the limits. The disintegration time was less than 15 minutes for different
formulations(15, 19) (Table 3)
The average weight, thickness, diameter and disintegration time were calculated for the soft
lozenges prepared by both cold extraction and maceration methods, and the results obtained were
tabulated. (Table 4) Since the mold used for both maceration and cold extraction were same,
hence their diameter and thickness differences were negligible .The average weight was more in
the tablets prepared by cold extraction (818.05mg) than maceration (770.33 mg), due to the high
density of cold extract when compared to the extract prepared by maceration. The same reason
could be attributed for longer disintegration time in the former (3-4 minutes) compared to the
latter (1.05 minutes).
The molecular analysis of compounds in alcoholic extract of Carica papaya was studied
using Gas Chromatography Mass Spectroscopy Analysis and the identified compounds were
listed in table 5 and the spectrum is shown in figure1. Around 24 compounds were identified in
the GC-MS spectrum of Carica papaya leaves extract. From the GC-MS analysis, it was
observed that 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, cis,cis,cis-7,10,13-Hexadecatrienal, n-
Hexadecanoic acid and 2-Pyrrolidinone were present in higher composition and had a maximum
peak area of 24.70% ,29.044%, 16.73% and 12.96 % respectively, while the other peaks had an
area lesser than 4% indicating the lower concentration. The GC-MS analysis of already existing
data reported that, the presence of 12 major compounds consisting of one piperidine alkaloid,
two organic acids, six malic acid derivatives, and four flavonol glycosides with a similar
spectrum (23).
D. Ramyadevi dkk /Int.J. PharmTech Res. 2014,6 (7), hlm 2083-2091. 2089
hexadecen-1-ol
24.
24. Y All-trans-Squalene C H 410 0,2571 43,41 481.199
30 50
XRF Analysis
From the XRF results of the Carica papaya leaf extract tablets, it was observed that,
elemental potassium (K) was present in high amount which was around 54.65 %, followed by
Magnesium (Mg) 12.10 %, Elemental copper and molybdenum which were present in low
quantity in the range of 0.08 %. In terms of oxide compounds, silicon-di oxide was found in high
percentage of about 25.21 % followed by Potassium oxide (K2O – 21.46%) and Copper (II)
oxide which has the least present oxide compound at 0.11 %(Table 6).From the previous studies,
it was found that, sodium was present in the highest quantity followed by potassium, while
phosphorous was found in least quantity. Among micro elements, Iron was found in highest
quantity while Boron was found to be the least (24).
S 2.42 Cl 4.36
From the obtained results of microbial limit test, it was found that total viable aerobic count
and total fungal count are within the limits as per the standard Indian Pharmacopoeia. All the
three microorganisms such as E Coli, Salmonella and Shigella were absent in the extract and
hence it was proved that the herbal formulation was safe to administer orally. (Table 7) Also the
stability of the formulation and sterility of processing conditions were identified to be
satisfactory.
D. Ramyadevi dkk /Int.J. PharmTech Res. 2014,6 (7), hlm 2083-2091. 2090
x 2 24,06,
14-Desember-2013 + 14:26:02
GC 3028 ekstrak etanol 14 12 13 Pindai EI + TIC
31,68
100
9.29e8
68
79
27,89
43
25,12
57
11,81%
30,65
69
58
71
19,84
19,01 70
16,66
27,60
44
191
44
149
0
Time10.90 15,90 20,90 25,90 30,90 35,90 40,90
Conclusion
The study involves the formulation of fresh leaf extracts of Carica papaya into a liqui-solid
compaction and soft lozenge formulation by both maceration and cold extraction methods. The
pre compression and post compression parameters of the tablets were found to be desirable. The
results of uniformity in weight, hardness test and friability test indicates its aptness for effective
packing, transport and marketing. The disintegration time within the standard limits ensures
perfect release of the active components in-vivo. Scale up studies can be performed for
application at industrial scale.
Acknowledgement
The authors are thankful to SASTRA University for providing the infrastructure with required
lab facilities and literature resources and also the continuous encouragement for successful
completion of the work.
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compression of tablets, Pharm Sci Technolo Today, 2000, 3, 58–63.
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2006.
18. The Indian Pharmacopoeia, Govt. of India. Ministry of Health and Family Welfare, the
Indian Pharmacopoeial commission, Ghaziabad, 2010, 1815-1817.
19. Dan, Shubhasis TKP, sustained release matrix tablet of diltiazem hydrochloride : formulation
development , in-vitro evaluation and statistical optimization by response surface methodology (
RSM ), 2013, 01, 6–22.
20. Bhan S, Rathore S, Sharma A, Garg A, Sisodiya DS, Formulation and evaluation of enteric
coated tablet of Ilaprazole, 2013, 2, 126–130.
21. Davis H. Secundum artem, Pharm J, 1948, 106, 233. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15369440.
22. The Pharmaceutics and Compounding Laboratory. Available at:
http://pharmlabs.unc.edu/labs/lozenge/objectives.htm.
23. Afzan A, Abdullah NR, Halim SZ, Repeated dose 28-days oral toxicity study of Carica
papaya L. leaf extract in Sprague Dawley rats, Molecules, 2012, 17, 4326–4342.
24. Hardisson A, Rubio C, Baez A, Martin MM, Alvarez R, Mineral composition of the papaya
( Carica papaya variety sunrise) from Tenerife island, Eur Food Res Technol, 2001, 212, 175–
181.