UNIVERSITAS INDONESIA

CONTROLLED DRUG RELEASE

DRUG RELEASE FORMULATION FOR SPINAL

TUBERCULOSIS

HOME GROUP 5
GROUP PERSONNEL:
CLARA NOVIA

(1306370985)

CLAUDIA MAYA I

(1306412180)

DAVID LAZUARDI

(1306370814)

PRATIWI ROSTININGTYAS

(1306370833)

MUHAMMAD FAHMI

(1206212520)

CHEMICAL ENGINEERING DEPARTMENT

ENGINEERING FACULTY
UNIVERSITAS INDONESIA
JUNE 2016

CHAPTER 1
INTRODUCTION
1.1.

BACKGROUND
Tuberculosis is one of the most prevalent disease in the world.

According to WHO report of Global Tuberculosis Report in 2015, the TB

cases are decreasing about 42% for the TB cases in 2015 than in 1990.
However, according to the same source, Indonesia is one of the three highest
country in TB cases, with TB cases about 10% of overall TB cases in the
world. And also, Indonesias actual TB cases is twice than the estimation by
the government.
In order to minimalize the epidemiology of TB in Indonesia, the
government had given the anti-TB drug for free in public health clinics.
However, another problem occurs from the patient. The patient is unable to
follow through the end of the doctor advice. Sometimes, the TB could come
back after some period in other form of diseases such as spinal TB, lymphoid
TB and other types of Mycobacterium infection. If a person is ill with spinal
TB and doesnt get the sufficient treatment, it could lead to fatally damage
the bone.
Concerned with these conditions, we would like to propose a way to
deal with spinal TB. We know that the patients tendency to stop consuming
the drug if they have already felt better is one of the most common problem
of spinal TB. Thats why we propose the application of implant in the
infected bone area. This implant could be loaded with anti-TB drug. By
using implant, there will be an increase of the drug bioavailability to the
bacteria which resulted in increase of efficiency and decrease in healing
time. Another advantage is there will be less dosing frequency which is the
best solution to the patients tendency. In this proposal, we design how to
create an anti-TB drug using implants We hope that this proposal could help
open the readers mind in curing spinal TB disease.
1.2. PROBLEM FORMULATION
1. Which drug that we need to use in order to cure Spinal Tuberculosis?
2. What kind of drug formulation that we need to create?
3. What material of implant that we need to create in order to achieve the
desired formulation?
4. How to create the implant?
CHAPTER 2
STUDY OF LITERATURE

2.1.
2.1.1.

SPINAL TUBERCULOSIS
Definition
Spinal TB or bone and joint TB is an infection caused by bacteria

Mycobacterium tuberculosis. It is classified as Extrapulmonary Tuberculosis (EPTB). It is

also popularly known as Potts Disease since it is originally described by Sir Percival Pott
in 1779. Potts disease is all about the destruction of other spinal elements, either severe
or progressive kyphosis. It described the TB infection of the spine and another term
Potts Paraplegia described the paraplegia symptom caused by spinal TB. The sickness
usually comes from Asian region and attacked people with age range from children until
40 years old. People began to beware of this disease since the epidemic of HIV infection
which cause resurgence (growth) in all form of TB. Commonly, TBs primary infection
site is the pulmonary lesion or infection of the genitourinary system. However, spinal TB
usually comes as a result of hematogenous spread (spread facilitated by blood) of M.
tuberculosis into the dense vasculature of cancellous bone of the vertebral bodies. The
bacteria spread via the arterial or venous route.
2.1.2.

Current Treatment Method

Nowadays, the treatment of spinal TB is given before and after surgical debridement.
Usually the treatment is classified based on the neurologic complication. For those
without neurologic deficit, the treatment will be mainly medical therapy but also in few
cases include the surgical interventions. On the other hand, those with neurologic deficit,
the medical therapy is the first choice but has higher success rate when combined with
surgical treatments. For medical therapy, the treatment commonly used combination of
rifampicin, isoniazid, ethambutol and pyrazinamide. Concerned with the increase of
Spinal TB infection, WHO designed a comprehensive drug treatment. First, WHO
divided the disease based on several categories, then they proposed a treatment regimen
for each category. Each category has 2 steps of drug treatment, the initial and
continuation phase.
2.2.

ACTIVE PHARMACEUTICAL INGREDIENT (API) COMPOUND

For the drug formulation, we proposed using the API for disease category
3 for extrapulmonary tuberculosis. Based on WHOs recommended treatment
regiment, for the initial phase we use Rifampicin, Isoniazid, Ethambutol and
Pyrazinamide for the first 2 months. Then we use Isoniazid and Rifampicin
for the next 4 months.

(a) Rifampicin

(b) Isoniazid

(d) Ethambutol
(c) Pyrazinamide
Figure 1. The Active Pharmaceutical Ingredients used in this formulation
Source : NCBI,2010

2.2.1. Rifampicin
Rifampicin is a semisynthetic antibiotic which is produced from
bacteria Streptomyces mediterranei. It has the molecular formula of
C43H58N4O12. It could works on both intracellular and extracellular organism. This
antibiotic has a broad antibacterial spectrum, including against several form of
Mycobacterium sp. It works by inhibiting DNA-dependent RNA polymerase activity by
forming stable complex with the enzyme. Then it suppress the beginning of RNA
Synthesis. Based on experiment, rifampicin is odorless, very stable in dimethyl sulfoxide
and rather stable in water. It is unstable in light, heat, air and moisture and soluble in
chloroform, ethyl acetate and methanol.
2.2.2. Isoniazid
A synthetic derivative of nicotinic acidwith anti-mycobacterial properties.
Appears to block synthesis of mycolic acid (major component of mycobacterial cell
wall). Isoniazid also interferes with mycbacterial metabolism of vitamin B6. Isoniazid ids
odorless, colorless, taste slightly sweet at first and then bitter, pH (1% aqueous solution)
5,5-6,5 and in 5% aqueous solution is 6-8, solubility in alcohol (25 0C); boiling alcohol;
and chloroform is 2%; 10%; and 0,1%, practically insoluble in eter and benzene.
Molecular formula C6H7N3O
2.2.3. Pyrazinamide

A synthetic pyrazinoic acid amide derivative with bactericidal property.

Particularly active against slowly multiplying intracellular bacilli by an unknown
mechanism of action. Its bactericidal action is dependant upon the presence of
bactericidal pyrazinamide (removes the amide group to produce active pyrazinoic acid).
One of the important component of multidrug theraphy for tuberculosis. Have molecular
formula C5H5N3O
2.2.4. Ethambutol
An anti tuberculant agent that inhibits the transfer of mycolic acid into the cell wall of
the tubercle bacillus. May also inhibit the synthesis of spermidine in mycobacteria. The
action is susually bactericidal and the drug can penetrate human cell membrane to exert
its lethal effect (Smith and Reynard, 1992)
Table 1. The Properties Of Rifampicin, Isoniazid, Pyrazinamid, And Ethambutol
Properties
Molecular Weight

Rifampicin
822.94022
g/mol

Isoniazid
137.13928
g/mol

Pyrazinamide
123.1127 g/mol

Ethambutol
204.30976
g/mol

XLogP3
Hydrogen Bond Donor
Count
Hydrogen Bond Acceptor
Count
Rotatable Bond Count
Exact Mass

4
6

-0.7
2

-0.6
1

-0.1
4

15

5
822.405123
g/mol

1
137.058912
g/mol

1
123.043262
g/mol

9
204.183778
g/mol

Monoisotopic Mass

822.405123
g/mol

137.058912
g/mol

123.043262
g/mol

204.183778
g/mol

Topological Polar Surface

Area
Heavy Atom Count
Formal Charge
Complexity

217 A^2

68 A^2

68.9 A^2

64.5 A^2

59
0
1750

10
0
120

9
0
115

14
0
109

Isotope Atom Count

Defined Atom
Stereocenter Count

0
9

0
0

0
0

0
2

Undefined Atom
Stereocenter Count

Defined Bond Stereocenter

Count

Undefined Bond
Stereocenter Count

Covalently-Bonded Unit
Count

(Source: NCBI,2010)

2.3. NON-API COMPOUND

2.3.1.
Type of API
According to patents code US20120027853 A1 from Taiwan Biotech Co. Ltd.,
the process further comprises a step of mixing the granules of step with excipients. There
are a few type of excipients that needs to be added and it can be seen in the table below.
Table 2. Type of Non-API
Type of Non-API
Binder Material

Purpose
This material helps hold such compositions together and release the

Inert Diluents

medicament therefrom
This material helps dissolving the API in order to simplify the mixing

Antioxidants

process
This material is used in order to prevent the oxidation of the API which
could change its molecular form thus resulting in change of physical and
chemical properties
These materials are agents added to tablet (and some encapsulated)

Disintegrants

formulations to promote the breakup of the tablet (and capsule slugs)

into smaller fragments in an aqueous environment thereby increasing the
available surface area and promoting a more rapid release of the drug
Lubricating Agent

substance
This material refers to a substance added to the dose to enable the dose,
e.g., a tablet, to be released from the mold or die after it has been

compressed.
(Source : Patent US20120027853 A1,2010)

2.3.2.

Material

For non-API material, herein refers to any material that is added to

pharmaceutical compositions to help hold such API composition together and release the
medicament therefrom. In this case we use Povidone as our binder material as the implant
itself must be water-insoluble for the pH environment which is at the spinal.
Povidone (polyvinylpyrrolidone, PVP) is used in the pharmaceutical industry as a
synthetic polymer vehicle for dispersing and suspending drugs. It also acts as a
disintegrant and tablet binder. It appears as white to off-white hygroscopic powder in its
pure form and is readily soluble in water. Povidone has the molecular formula of
(C6H9NO)n. Povidone formulations are widely used in the pharmaceutical industry due
to their ability to dissolve in both water and oil solvents.
According to the present invention, the binder material is dissolved in organic
solvents including but not limited to high-concentration alcohol. Preferably, the
concentration of alcohol is at least about 95%. More preferably, the concentration of
alcohol is 99.5%.

2.4.

BIO-CERAMICS IMPLANT

Bio-ceramics, such as calcium phosphate ceramics and cements and silica-based

glasses, are widely used as components of implants for bone and teeth restoration. Bioceramics act as local drug delivery systems to treat large bone defects, osteoporotic
fractures, bone infections and bone tumors. The development of new meso-porous nanoceramics, suitable to be used as carriers for drug delivery (Arcos, et al., 2013).

Figure 2. Bio- ceramics for Drug Delivery

Source: http://remote-lib.ui.ac.id:2057/science/

2.4.1. Shape of Implants

This implants can application for drug carrier that has more benefit because this implant
is biodegradable and biocompatible. The biodegradable implant comprises a matrix
structure in which the drug to be released in distributed throughout in the desired
concentration. The table A.1 in the appendices may can explain about overall implants.
2.4.2. Thickness of Implants
We are use bio ceramics for implants, if we use that, we must know about
biodegradability and biocompatibility of bioceramics in the body. The sufficient time for
the complete degradable of bioceramics within the body is 220 days which has various
thickness as shown in table below (Sidman, 1973). If the implants has thickness of 0,3
mm, we know that the biomaterials can biodegradable in the body based on patent
(Kenneth R. Sidman, 1973).

Table 3. Characteristic of Bio Ceramics

(Source: www.google.com/patents/US4351337)

2.4.3. Time of Biodegradation

More benefits of implant from bio-ceramics is because the material is biodegradable in
the body, this figure explain about time of biodegradable bio-ceramics that application in
drug delivery.

Figure 3. Biodegradable of Implant

Source : http://remote-lib.ui.ac.id:2057/science/

CHAPTER 3

METHOD OF FORMULATION
3.1.
3.1.1.

Manufacturing Process
Ingredients
Table 4. Drug Formulation

Ingredients
Isoniazid
Rifampicin
Pirazinamid
Entambutol
Total (mg)
Total (g)
Providine (g)
Total (g)
3.1.2.

Drug Formulation
Layer 1 (mg)
Layer 2 (mg)
Active Ingredients
2160
270
3780
945
0
1350
0
675
5940
3240
5,94
3,24
Excipient Ingredient
1,98
1,08
7,88
4,32

Drug Manufacturing Process

For the manufacturing process of the drug until ready for market, the flow
of the processes involved can be quite simple, because the final form of this TBC
bone drug is implant in the bone. Here is a process flow diagram for a
manufacturing process.
Ingredients
Sterilization

Mixing of
Ingredients

Sterilization

Insert in
Implant

Figure 4. Flow Diagram for manufacturing Process

Based on the above flowchart, it is known that the process flow for drug
manufacturing process is as follows : sterilization, mixing, sterilization, insert in
implant. Firstly, the sterilization unit is intended to eliminate the possibility of
contamination biologically and chemically. One effective way is by using heat (or
heat exchange evaporation method), with coagulation, or by any other method.
This sterilization stage must be differentiated conditions and manner for each
material, that the raw materials are not damaged as a result of the treatment is
done. Then, the next process in main mixing. In this unit, the mixing ratio of
materials to one another is based on optimal composition that has been determined

from the test lab, so it can be said that this tool functions as a unit weighing
concurrently. After mixing all ingredients, we need to sterilize the product again in
order to eliminate the possibility of contamination biologically and chemically.
Lastly, the drug formulations that have been formed, need to be incorporated into
the implant.
3.1.3.

Implant Manufacture

Based on patent (Kenneth R.Sidman, 1973), implant material/copolymer used

must posses certain properties (biodegradebility and biocompatibility). One of
material is poly--amino acid. The quantity of copolymer depends on the rate and
the length of drug which it is to be released.
After implant material was chosen, implant material blend with drug as the
core and then forming the desired structural shape with heat and pressure, the
fabrication conditions being such as not to destroy the efficacy of the drug or to
degrade the matrix material. We chose rod form because it provides a
concentration gradient which increases from the outermost to core in which the
core was the drug itself. Scan using electron microscope of the surface and of
cross section to showed no evidence of separate drug and copolymer phase.
Lastly, we need to sterilize it. Alcohol is used as sterilizer and then rinse with salt
solution.
3.2.
3.3.

Drug Formulation Testing

Economic Analysis

CHAPTER 4
CONCLUSION
Based on the previous chapters, we can conclude that :
1. Current Spinal Tuberculosis treatment is ineffective because of the
patients tendency not to follow through the doctors advice
2. One of the idea that we can use in order to overcome this problem is by
using drug incorporated in implant which has higher drug bioavailability
and less dosing frequency
3. The implant is made of

bioceramic

which

is

biodegradable

and

biocompatible with human body

4. The drug substance that can be used is isoniazid, rifampicine, ethambutol,
and pyrazinamide. These drug is combined using povidone as its binder.
5. There are 2 steps that we need to do in order to create the implant : drug
mixing and implant manufacturing.
6. After creating the implant, we need to evaluate its formulation by
7. Based on its price, our product is

REFERENCE
Anonymous [Online]. - May 18, 2016. - http://eprints.ums.ac.id/16035/4/BAB_I.pdf.

Arcos Daniel and Regi Maria Vallet Bioceramics for Drug Delivery [Journal] // Acta
Materialia. - 2013. - 3 : Vol. 61. - p. 1.
Ethambutol [Online] // NCBI (National Center for Biotechnology Information) PubChem
Compound Database). - 2010. - May 11, 2016. https://pubchem.ncbi.nlm.nih.gov/compound/14052.
Jawahar M.S. Current trends in chemotherapy of tuberculosis [Journal]. - [s.l.] : Indian J
Med Res, 2004. - O : Vol. 120.
Li-Heng Pao Nion-Heng Shiao, Kuo-Hua Yang, Jui-Ming Chou Process for
preparation of anti-tubercular combination and pharmaceutical composition prepared
therefrom [Patent]. - USA, February 2, 2012.
Paramarta I Gede Epi [et al.] [Online]. - October 3, 2008. - May 18, 2016. http://saripediatri.idai.or.id/pdfile/10-3-6.pdf.
Pyrazinamide [Online] // NCBI (National Center for Biotechnology Information)
PubChem Compound Database. - 2010. - May 11, 2016. https://pubchem.ncbi.nlm.nih.gov/compound/1046.
Pyrazinamide [Online] // NCBI (National Center for Biotechnology Information)
PubChem Compound Database.. - 2010. - May 11, 2016. https://pubchem.ncbi.nlm.nih.gov/compound/1046 .
Rifampicine [Online] // NCBI (National Center for Biotechnology Information)
PubChem Compound Database. - 2010. - May 11, 2016. https://pubchem.ncbi.nlm.nih.gov/compound/5381226.
Sidman Kenneth R Biodegradable Implantable Drug Delivery Device, and Process for
Preparing and Using the Same [Patent]. - Mei 17, 1973.

APPENDICES

APPENDIX A
Table A1. Shape of Implant
Figure

Information
Illustrates an essentially two-dimensional implant
device particularly suitable for in vivo testing.

Illustrates an implant device constructed in accordance

with this invention in the form of a rod.

Illustrates an implant device in the form of a hollow

cylinder.

Illustrates an implant device in the form of a layered rod

in which the drug concentration is different from its
adjacent layer or layers to achieve a predeter mined rate
of drug release.
Illustrates an implant device in the form of a rod with a
core containing a drug different from the surrounding
layer.
Illustrates an implant device of a rod configuration
which is a closed tube containing all, or most, of the
drug within the tube
Transverse cross section of the closed tube.

shows a microcapsule implant constructed in accordance

with this implant.

(Source: Patents US4351337,2010)