Title of Invention

"A PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION OF ANTI-TUBERCULAR DRUGS FOR ORAL USE"

Abstract Process for the preparation of a pharmaceutical composition of anti-tubercular drugs for oral use comprising treating Rifampicin and/or Isoniazid, in delayed release form or extended release form with pH senstive or pH independent polymers, as herein described, by conventional techniques and mixing the treated Rifampicin and Isoniazid whereby the bioavailability of Rifampicin is enhanced by preventing its degradation caused by presence of Isoniazid and optionally adding conventional buffers and bioavailability enhancing agents to the composition prepared.
Full Text Tuberculosis is a major problem largely of developing countries but lately emergence of Mycobacterium infections in HIV infected individuals is also on the rise in developed countries. The management of tuberculosis treatment is further complicated due to emergence of drug resistance. Drug resistance in tuberculosis is due to inappropriate prescribing or taking of medications, effectively resulting in monotherapy. To reduce the possibility of monotherapy, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Diseases (IUATLD) have recommended that antitubercular drugs should be taken in combination (Fixed dose combination tablets for the treatment of tuberculosis, Report of an informal meeting held in Geneva 27 April 1999, World Health Organization Communicable Diseases Cluster, 1999). A number of combinations of first line drugs containing rifampicin, isoniazid, pyrazinamide and ethambutol. This fixed dose combination (FDC) tablets provide a simple approach to delivering the correct number of drugs at the correct dosage as all the necessary drugs are combined in a single tablet. By altering the number of pills according to the patient's body weight, complete treatment is delivered without the need for calculation of dose. However, such FDC tablets are not free from disadvantages. The major issue is the adverse effect on bioavailability of rifampicin in presence of other drugs. Various researchers have worked on several aspects of this problem of FDC tablets and several recommendations are recorded in literature. WHO attributes that when rifampicin combined with the other drug within the same formulation the bioavailability negatively affected if the manufacturing procedures are not strictly controlled. Against this background, WHO and IUATLD issued a joint statement in 1994 advising that only FDC tablets of good quality and proven bioavailability of rifampicin should be used in the treatment of tuberculosis (Anonymous; 1994; Tuber. Lung Dis.; 75: 180-181). There are several forthcoming articles in a special supplement of the International Journal of Tuberculosis and Lung disease devoted to the quality assurance of FDC tablets. These include a simplified protocol for assessing rifampicin bioavailability and its use in studies carried out in South Africa and India (Ellard, G.A.; 1999; Int. J. Tuberc. Lung Dis.; Nov 3; H; Suppl. 3 : S284-5; Mclleron, H. et al.; 1999; Int. J. Tuberc. Lung Dis. 1999; Supplement; in preparation;
Panchagnula, R. et al.; 1999; Int. J. Tuberc. Lung Dis.; Supplement; in preparation), high performance liquid chromatographic methods for assaying of rifampicin, isoniazid and Pyrazinamide (Smith, P. et al.; 1999; Int. J. Tuberc. Lung Dis.; Supplement; in preparation) procedures for ensuring laboratory proficiency for rifampicin bioavailability studies (Ellard, G.A.; 1999; Int. J. Tuberc. Lung Dis.; Supplement; in preparation) improved procedure of dissolution testing of rifampicin in presence of isoniazid (Shishoo, C.J. et al.; 1999; Int. J. Pharm.; Nov 10; 190 (1) : 109-23) and a review of the pharmacology of rifampicin (Ellard, G.A. et al.; 1999; Int. J. Tuberc. Lung Dis.; Nov 3; j_l Suppl 3; S301-8 : S317-21).
It has been reported that the poor absorption of rifampicin from combination products may be due to decomposition of the drug in acidic stomach conditions, which is accelerated in the presence of isoniazid (Shishoo, C.J. et al.; 1999; Int. J. Pharm.; Nov 10; 190 (1): 109-23; Singh, S. et al ; 2000 ; Pharm. Pharmacol.Commun: 6 : 491-494). The mechanism of this degradation was proposed by Singh et al.(Singh, S. et al.2000: Pharm. Pharmacol. Commun.:_6_L 405-410). Studies revealed that the decomposition of rifampicin in acidic conditions in the absence of isoniazid stopped at the formation of 3-formylrifamycin, while the reaction in the presence of isoniazid proceeded to form a hydrazone between 3-formylrifamycin and isoniazid. Further, it was suggested that once 3-formylifamycin is formed, it interacts with isoniazid to form the hydrazone, though a fast second order reaction. As hydrazone are unstable in acid conditions, 3-formylrifamycin and isoniazid are regenerated in a reversible manner through a slower first order reaction. In this complex reaction process rifampicin is further degraded, while isoniazid is recovered.
Devani et al. (Devani, M.B. et al.; 1985; J. Pharm. Sci.; 74 : 427-432), has also discussed kinetics of hydrazone formulation from isoniazid in presence of reducing sugars.
None of the reports has suggested a pharmaceutical technological solution to the above problem. The inventors after careful experimentation and expenditure of considerable amount of mental faculties and time have found a novel way to solve the bioavailability problems of drugs in FDC tablets.
The invention described herein discloses compositions of anti-tubercular drugs where attempts have been made to prevent the loss in bioavailability of rifampicin in presence of isoniazid.
During experimentation the inventors have found that the degradation of rifampicin is pH dependent in presence of isoniazid. At pH around 1 the degradation is minimum and increases abruptly as pH ranges between 2 and 3. Thereafter, above pH 3 the degradation is minimal.
The pH of the gastric contents is normally between 1 and 3 which results in significant degradation of Rifampicin when administered orally alongwith other anti-tubercular agents, in particular Isoniazid.
This problem has been solved by controlling the release or dissolution of both the drugs in such a way that the release takes place at different locations inside the gastrointestinal tract without compromising the total bioavailability of either of the drugs. It means that the two drugs i.e. rifampicin and isoniazid do not come in contact with each other in solution state in the gastrointestinal tract thereby preventing the interaction. The composition may also include other known anti-tubercular drugs like Ethambutol Hydrochloride and Pyrazinamide.
The site-specific release of active ingredients has been achieved by various techniques like
a) Controlling release of rifampicin and isoniazid at different locations in the
gastrointestinal tract by use of pH sensitive materials
b) Controlling dissolution of drugs by forming barrier coat and/or matrix with pH
insensitive materials such that the contact of rifampicin and isoniazid in
solution state is avoided.
c) Using different crystal forms of the drugs such that there is significant
difference in dissolution rate of the drugs.
d) Modifying the surfactant action of rifampicin with use of materials like
Methylpolysiloxane, natural and synthetic oils. Use of such materials reduces
the surfactant action with corresponding reduction in solubility of rifampicin.
Preferably the drug is modified such that the release takes place at pH of approximately 5.0. At pH 5.0 the drug release takes place very rapidly such that there is no loss of bioavailability, Whereas the other drug or drugs are released in the more acidic (pH 1.0 - 3.0) environment of stomach.
Further, the invention discloses the Fixed Dose Combination of anti-tuberculosis drugs in oral suspension form. Suspension type dosage forms are of particular importance for fixed dose combination where the total amount of active ingredients of a single
/
dose becomes very high. Such highdoses cannot be filled into hard or soft gelatin capsules. Even compressed tablets become too big and are very difficult to swallow.
It has surprisingly been found in the present invention that it is
I,
possible to conveniently administer such high dose combinations of anti-tubercular drugs wherein one or more active ingredients may be present in extended or delayed release form, in the form of oral suspension leading to no loss of bioavailability of any of the actives. This has been achieved by making molecular dispersion of Rifampicin and/or Isoniazid having pH dependent release characteristics even when finely powdered. Such powders can be blended with other drugs and compressed into tablets or made into suspensions alongwith the other drugs. Another advantage is minimal increase in size of tablets which is serious problem for high dose drugs.
Accordingly the present invention provides a process for the preparation of a pharmaceutical composition of anti-tubercular drugs for oral use comprising Rifampicin and Isoniazid in delayed release form or extended release form characterised in that Rifampicin and/or Isoniazid is treated with pH sensitive or pH independent polymers, as herein described, by conventional techniques whereby the bioavailability of Rifampicin is enhanced by preventing its degradation caused by presence of Isoniazid and optionally adding conventional buffers and bioavailability enhancing agents to the composition prepared.
According to one embodiment, Rifampicin is in delayed release or extended release form.
According to another embodiment, Isoniazid is in delayed release or extended release form.
The conventional buffers are added to the composition to raise the pH of the gastric contents beyond 3.
Further the active ingredients may be in taste masked form. Such dosage forms will be highly desirable for treatment of tuberculosis in masses and reduction in the development of drug resistance which commonly occurs due to non compliance of existing type of dosage forms.
The active ingredients may be having barrier coating to prevent drug-drug/excipients interactions.
The suspension may be in ready-to-use form or to be reconstituted before use. Preferably the ready-to-use suspensions will have non-aqueous base/carrier, suitable examples of suspension bases include glycols and glycol derivative;
Propylene carbonate; glycerol; oils of animal, vegetable or mineral origin; medium chain triglycerides; transesterification products of natural vegetable oils with alkylene polyols; Esters of polyols with fatty acids.
Other ingredients of the suspension dosage form includes suspending agents, viscosity imparting agents, anti-caking agents, sweeteners, flavors, coloring agents and the like, known to persons skilled in the art.
The polymers used to modify the release of drugs may be natural, semi-synthetic,
synthetic or man-modified. Suitable materials include cellulose and ceiiuiose
derivatives like microcrystalline cellulose, methyl cellulose, ethyl cellulose,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate,
cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose
acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropyl
methylcellulose phthalate , hydroxypropyl methylcellulose acetate succinate.
Polyethylene; Polyquaternium-1; Polyvinyl acetate (homopolymer); Polyvinyl acetate
phthalate; Propylene glycol alginate; PVM/MA copolymer; PVP/
dimethiconylacrylate/polycarbamyl/polyglycolester; PVP/ dimethylamino
ethylmethacry- late copolymer; PVP/dimethylaminoethylmethacrylate/ polycarbamyl polyglycol ester; PVP/polycarbamyl polyglycol ester; PVP/VA copolymer Lanolin and lanolin derivatives, buffers, lipophilic materials like, fats, fatty acid glycerides, oleic acid, cholesterol, transesterification products of polyols with fatty acids, glyceryl monostearate, stearic acid, paraffins, beeswax, carnauba wax, tribehenin. Polyalkylene polyols like polyethylene glycols. Gelatin and gelatin derivatives. Alginates. Carbomers. Polycarbophils. Methacrylic acid copolymers. Carrageenans, pectins, chitosans, cyclodextrins, lecithins. Natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guar gum, etc. Ion exchange resins like polacrilin pottasium, acrylic acid copolymers, sodium polystyrene sulphonate, polystyrene copolymers and the like. Buffers like sodium dihydrogen orthophosphate, disodium hydrogen phosphate, di-potasium hydrogen phosphate, potassium dihydrogen orthophosphate, borate buffer, phthalate buffer, oxalate buffer and the like.
In another embodiment of the invention, the active ingredient may be present in micronized form to achieve faster absorption. Micronisation may be carried out by processes like air jet milling, ball mill and the like. The average particle size should be less than 5 microns.
Further the invention also discloses use of bioavailability enhancers like piperine and its derivatives, Ayurvedic preparations like trikatu alongwith the compositions of present invention may also help in increasing bioavailability.
The invention is further described with the help of following examples which should not be construed as limiting the scope of invention :
1. Microenoapsulation of Rifampicin
Cellulose Acetate Phthalate 64 g
Rifampicin 800 g
Polyethylene Glycol 4000 6.4 g
Water 1200 ml
Hydrochloric Acid 0.5 ml
Dichloromethane 200 ml
Isopropyl Alcohol 100 ml
Procedure
1. Dissolve Cellulose Acetate Phthalate and Polyethylene Glycol 4000 in
Isopropyl Alcohol & Dichloromethane mixture
2. Disperse rifampicin in water containing 0.5 ml of Hydrochloric Acid to make a
slurry and keep on a water bath at 50"C.
3. Add CAP solution to the slurry with constant stirring.
4. Filter off the microcapsules and dry them.
The above mentioned microcapsules of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
2. Microencapsulation of Rifampicin
Sodium Alginate 20 g
Rifampicin 100 g
Calcium Chloride Solution 5% w/v
Water 500 ml
Procedure
1. Dissolve Sodium Alginate in Purified Water.
2. Disperse rifampicin in above solution.
3. Add the above suspension dropwise to Calcium Chloride Solution with
constant stirring.
5. Filter off the microcapsules and dry them.
The above mentioned microcapsules of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
3. Preparation of Microcapsules of Rifampicin
Rifampicin 100 g
Ethyl Cellulose M20 100 g
Water 600 ml
Dichloromethane 300 ml
Procedure
1. Dissolve Ethylcellulose in dichloromethane.
2. Disperse Rifampicin in water and keep in a water bath at 40°C.
3. Add solution of Ethylcellulose to drug slurry with constant stirring.
4. Filter off the microcapsules and wash with water and allow to air dry.
The above mentioned microcapsules of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
4. Microspheres of Rifampicin
Chitosan 500 mg
Pluronic F68 2 g
Rifampicin 10 mg
Sodium Tripolyphosphate (as 10% w/v solution in water) 10 g
Water 200 ml
Procedure
1. Dissolve Chitosan in acetic acid containing Pluronic F-68 as surfactant.
2. Add 10 mg drug into Chitosan solution. Then add Sodium Tripolyphosphate
dropwise with vigorous shaking. A cloudy suspension is formed as a result of
crosslinking and precipitation of Chitosan microspheres.
3. Centrifuge the microspheres at 3000 rpm for 10 minutes and wash the pellets
twice with deionized distilled water and dry them.
The above mentioned microspheres of Rifampicin may be blended with other anti-
tubercular drugs and suitable excipients to formulate into tablets, capsules or
suspension.
6. Micospheres of Rifampicin
Rifampicin 10 g
AgarAgar 4 g
Citric Acid 2 g
Water 50 ml
Polyvinyl Alcohol 15 g
Ethanol 100 ml
Procedure
1. Dissolve Citric Acid in Water and disperse Rifampicin, and Agar Agar in it
with constant stirring.
2. Meanwhile, dissolve Polyvinyl Alcohol in Ethanol.
3. Add the aqueous solution to the alcoholic solution of Polyvinyl Alcohol with
constant stirring.
4. Evaporate to dryness and separate the microspheres. Such microspheres can
be formulated in suspension type dosage form as exemplified below:
Rifampicin 0.200 g
(In microspheres form as per example 5)
Isoniazid (in taste masked form
as per example 39) 0.300 g
Pyrazinamide 0.750 g
Ethambutol Hydrochloride(in taste masked
form as per example 28) 0.400 g
Aspartame 0.025 g
Labrafac PG (Gattefosse, France) 5.000 g
Corn oil 3.000 g
Butylated Hydroxyanisole 0.0015 g
Flavour 0.097 g
Procedure
1. Mix Labrafac PG and Corn oil and dissolve Butylated Hydroxyanisole in it.
2. Then add Rifampicin, Isoniazid, Pyrazinamide, Ethambutol Hydrochloric
Flavour and Aspartame to the bulk with stirring.
6. Bilayer tablet
Layer -1
Rifampicin 0.225 g
Hydroxypropyl methyl Cellulose Phthalate 0.050 g
Isopropyl Alcohol 2.000 g
Layer - II
Isoniazid 0.150 g
Pyrazinamide 0.750 g
Ethambutol Hydrochloride 0.400 g
Starch 0.075 g
Water 0.500 g
Procedure
1. Granulate Rifampicin with solution of Hydroxypropylmethylcellulose Phthalate
in Isopropyl Alcohol and dry them.
2. Separately, granulate Isoniazid, Pyrazinamide, Ethambutol Hydrochloride with
Starch Paste in water and dry them.
3. Compress the granules into Bilayered tablets on a rotapress. Isoniazid (Layer
- II) is immediately released. Rifampicin layer is released in delayed form in
pH 5.5 and above.
7. Enteric Coated beads of Rifampicin
Rifampicin 0.5 Kg
Non-pareil beads 1.2 Kg
Polyvinyl Pyrrolidone 0.100 Kg
Isopropyl Alcohol 7.00 L
EudragitLlOO 0.40 Kg
Acetone 6.00 L
Water 1.00 L
Triethyl Citrate 0.04 Kg
Procedure
1. Prepare The enteric coated beads of Rifampicin using fluid bed coater.
2. Spray dispersion of Rifampicin and Polyvinyl Pyrrolidone in Isopropyl Alcohol
onto the fluidized non pareil beads.
3. Spray dispersion of Eudragit L100 and Triethyl Citrate in water/Acetone
mixture on the rifampicin beads.
Such beads may be used in conjunction with other drugs to make formulations as examplified below:
(i) Rifampicin 600 mg
(In enteric coated bead form as per example 6)
(ii) Isoniazid 150 mg
Mix (I) and (ii) and fill in hard gelatin capsules, or mix (I) and (ii) with suitable lubricants and diluent like lactose, microcrystalline cellulose and compress into tablets or fill in hard carpsules.
8. Rifampicin Granules (delayed release)
Rifampicin 9.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 1.00 Kg
Acetone 3.0 L
Water 0.5 L
Procedure
1. Dissolve Eudragit L 100 in mixture of acetone and water.
2. Granulate Rifampicin in a rapid mixer granulator with the above solution. Sift
the wet mass through 10 mesh screen and dry.
3. After drying the granules, sift the granules through 30 mesh screen. Such
granules may be added to a oral suspension or capsule or compressed into
tablets alongwith other active agents and excipients.
The above mentioned granules of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
9. Molecular dispersion of Rifampicin with enteric (delayed release) effect
Rifampicin 9.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 0.50 Kg
Cellulose Acetate Phthalate 1.00 Kg
Isopropyl Alcohol 5.0 L
Methylene chloride 10.0 L
Procedure
1. Dissolve Eudragit L 100 and Cellulose Acetate Phthlate in mixture of Isopropyl
Alcohol and Methylene Chloride separately. Mix both the solutions.
2. Dissolve Rifampicin in Methylene Chloride and add to the above solution and
mix for one hour.
3. Evaporate the solvents on a water bath and pass the residue through a sieve
of mesh size 100.
The above mentioned powder of Rifampicin has almost no release in acid stage i.e. pH 1 - 3 for upto 2 hours. Whereas above pH 5.5 more than 85% of drug is released in about 45 minutes. This powder may be blended with other anti-tubercular drugs and suitable excipienta to formulate into tablets, capsules or suspension. Upon compression, there is no change in release of rifampicin during acid stage.
10. Molecular dispersion of Rifampicin with enteric (delayed release) effect
Rifampicin 8.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 0.50 Kg
Polyvinyl Acetate Phthalate 0.75 Kg
Isopropyl Alcohol 4.0 L
Dichloromethane 8.0 L
Procedure
1. Dissolve Eudragit L 100 and Polyvinyl Acetate Phthalate are in mixture of
Isopropyl Alcohol and Dichloromethane separately. Mix both the solutions.
2. Dissolve Rifampicin was dissolved in Dichloromethane and add to the above
solution and mix for one hour.
3. Evaporate the solvents on a water bath and pass the through a sieve of mesh
size 100.
The above mentioned powder of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
11. Molecular dispersion of Rifampicin with enteric (delayed release) effect
Rifampicin 2.00 Kg
Shellac 0.10 Kg
Isopropyl Alcohol 1.0 L
Methylene Chloride 2.0 L
Procedure
1. Dissolve Shellac in a mixture of Isopropyl Alcohol and Methylene Chloride separately.
2. Dissolve Rifampicin in Methylene chloride and add to the above solution and
mix for two hours.
3. Evaporate the solvents on a water bath and pass the residue through a sieve
of mesh size 100.
The above mentioned powder of Rifampicin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
12. Rifampicin Granules (delayed release)
Rifampicin 2.00 Kg
EudragitLSOD 0.20 Kg
Purified Water 0.50 L
Procedure
1. Dilute Eudragit L 30 D with Purified Water.
2. Granulate Rifampicin with the above solution in a mass mixer for 1.5 - 2.0 h.
3. Pass the wet mass through multimill and dry the granules.
An oral suspension using such granules is described below :
Oral Suspension
Rifampicin 225 mg
(In delayed release granule form as per example 12)
Isoniazid 150 mg
(In taste masked form for taste masking
as per example 39)
Ethambutol Hydrochloride 400 mg
(in ion-exchange complexed form for taste
masking as per example 28)
Pyrazinamide 750 mg
Colloidal Silicon Dioxide 100 mg
Aspartame 20 mg
Flavour q.s
Medium Chain Triglyceride q.s to 10 ml
Procedure
Disperse Colloidal Silicon Dioxide, Aspartame in Medium chain triglyceride. Add rifampicin granules, Isoniazid, Ethambutol Hydrochloride and Pyrazinamide and flavour with stirring.
13. FDC Formulation containing piperine as absorption enhancer
Rifampicin 225 mg
(In delayed release granule form as per example 12)
Piperine 60 mg
Isoniazid 150 mg
(In taste masked form for taste masking
as per example 39)
Ethambutol Hydrochloride 400 mg
(in ion-exchange complexed form for taste masking
as per example 28)
Pyrazinamide 750 mg
Colloidal Silicon Dioxide 100 mg
Aspartame 20 mg
Flavour q.s
Medium Chain Triglyceride q.s to 10 ml
Procedure
Disperse Colloidal Silicon Dioxide, Aspartame in Medium chain triglyceride. Add rifampicin granules, Piperine, Isoniazid, Ethambutol and Pyrazinamide and flavour with stirring.
14. pH sensitive fast release granules of Rifampicin
Core
Rifampicin 20 parts
Low substituted Hydroxypropyl Cellulose 52 parts
Lactose 13 parts
Hydroxypropyl Cellulose 5 parts
Alcohol 20 parts
Film
Eudragit L 100 5.5 parts
Isopropyl Alcohol 60.2 parts
Acetone 33.5 parts
Dibutyl Phthalate 0.8 parts
Procedure
1. Mix Rifampicin, Low substituted Hydroxypropyl Cellulose, Lactose.
2. Granulate the above bulk with alcoholic solution of Hydroxypropyl Cellulose.
3. Dry the granules and sift through mesh 60.
4. Coat the granules with enteric film forming solution of Eudragit L 100 and
Dibutyl Phthalate in Isopropyl Alcohol and Acetone using fluid bed coater.
Such granules may be used to make capsules, tablets or oral suspension.
15. Millispheres of Rifampicin
Phase -1
Rifampicin 10 g
Sodium Alginate 20 g
Water 90 g
Phase - II
Chitosan 5 g
Calcium Chloride 5 g
Water 200 ml
Prepare Phase - I solution by dispersing Rifampicin and Sodium Alginate in Water. Dissolve Chitosan, Calcium Chloride in water to prepare Phase - II. Add Phase - I dropwise with stirring to Phase - II. Soft millispheres of rifampicin are formed. Separate by filteration and dry under vacuum.
Such millispheres may be used to formulate oral suspension dosage form alongwith other anti - tubercular agents.
16. Rifampicin in Lipophilic Matrix
Rifampicin 5.0 Kg
Glyceryl Monostearate 2.0 Kg
Poloxamer188 0.1 Kg
Lactose 2 Kg
Ethyl Cellulose 0.5 Kg
Alcohol 2.0 L
Procedure
1. Dissolve Glyceryl Monostearate and Poloxamer in Alcohol and heat up to
70°C so as to obtain a clear solution.
2. Add drug to the bulk and cool.
3. Evaporate the alcohol and granulate the residue with Lactose as diluents and
Ethyl Cellulose as binder.
Such granules may be used to formulate a tablet, capsule, dosage form or oral suspension dosage form alongwith other anti - tubercular agents.
17. Rifampioin in Carbomer Matrix
Rifampicin 5.0 Kg
Carbomer (Carbopol 934P, BF Goodrich) 1.0 Kg
Lactose 5.0 Kg
Ethyl Cellulose 0.5 Kg
Acetone 2.0 L
Alcohol 10.0 L
Water 5.0 L
Procedure
1. Dissolve the drug in alcohol and Carbopol in water. Mix both the solution and
keep aside for one hour.
2. Evaporate the solvents and pulverised the mass into powder and granulate with
Lactose as diluent and Ethyl Cellulose in Acetone as binder.
Such granules may be used to formulate a tablet, capsule, dosage form or oral suspension dosage form alongwith other anti - tubercular agents.
18. Mesosomes of Rifampicin
Rifampicin 2.0 Kg
Glyceryl Monostearate 1.0 Kg
Palmitic Acid 0.5 Kg
Tween 60 0.1 Kg
Water 5.0 L
Melt Glyceryl Monostearate and Palmitic Acid in a water bath and disperse drug in it. Pour the molten mass to hot purified water containing Tween 60 under stirring. Then add this to ice chilled water with continuous stirring. Filter the mesosomes and air dry them.
The above mentioned mesosomes of rifampicin may be blended with anti tubercular drugs and suitable excipients to formulate into tablets, capsules or suspensions
19. Tablet- in-tablet formulation (rifampicin in delayed release form)
Core tablet Per tablet
Rifampicin 225 mg
Starch 20 mg
Lactose 28 mg
Water
Magnesium Stearate 10 mg
Sodium Lauryl sulphate 10 mg
Sodium Starch Glycollate 30 mg
Pass Rifampicin and Lactose through sieve and granulate with Starch Paste and pass through multimill. Dry the granules at 50° to 60°C and pass through sieve of mesh size 18. Pass Sodium Starch Glycollate, Sodium Lauryl Sulphate and Magnesium Stearate through sieve of mesh size 40 and mix with the dried granules and compress.
Enteric Coating of Rifampicin Tablets (Batch Size 2.0 Kg)
Eudragit L 100 88.00 g
Purified Talc 20.00 g
Triethyl Citrate 18.00 g
Dichloromethane 1.30 L
Isopropyl Alcohol 0.60 L
Dissolve Eudragit L 100 in Isopropyl Alcohol and dichloromethane mixture. Add
Triethyl Citrate and Talc to the above bulk and mix for 45 minutes. Coat the tablets to
a weight build up of 6 - 8% w/w.
Outer Tablet
Pyrazinamide 750 mg
Ethambutot Hydrochloride 400 mg
Isoniazid 150 mg
Magnesium Stearate 10 mg
Sodium Starch Glycollate 30 mg
Lactose 65 mg
Povidone 50 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid and lactose through a sieve and granulate wrth Povidone solution in water. Pass the wet mass through multimill and dry the granules 50 - 60° C. Pass dried granules through sieve of mesh size 16. Pass Magnesium Stearate and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules. Compress into tablets alongwith the Rifampicin enteric coated tablets in between.
Film Coating of outer tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
20. Tablet- in-tablet formulation (Isoniazid in delayed release form)
Core tablet Per tablet
Isoniazid 150 mg
Lactose 30 mg
Starch 5 mg
Water
Magnesium Stearate 3 mg
Purified Talc 3 mg
Pass Isoniazid and Lactose through sieve and granulate with Starch paste and pass through multimill. Dry the granules at 50° to 60°C and pass through sieve of mesh size 18. Pass Magnesium Stearate and Talc through sieve of mesh size 60 and mix with the dried granules and compress.
Enteric Coating of Isoniazid Tablets (Batch Size 2.0 Kg)
Hydroxypropylmethyl Cellulose Phthlate 80.00 g
Purified Talc 25.00 g
Dibutyl Sebacate 15.00 g
Dichloromethane 1.30 L
Isopropyl Alcohol 0.60 L
Dissolve Hydroxypropylmethyl Cellulose Phthlate in Isopropyl Alcohol and Dichloromethane mixture. Add Dibutyl Sebacate and Talc to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 4 - 6% w/w.
Outer Tablet
Pyrazinamide 750 mg
Ethambutol Hydrochloride 400 mg
Rifampicin 225 mg
Lactose 70 mg
Magnesium Stearate 10 mg
Sodium Starch Glycollate 15 mg
Povidone 30 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochioride, Rifampicin and Lactose through a sieve and granulate with Povidone solution in water. Pass the wet mass through multimill and dry the granules at 50 - 60' C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules. Compress the tablets alongwith the Isoniazid enteric coated tablets in between.
Fiim Coating of outer tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Gtycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
21. Tablet formulation containing Isoniazid in Delayed Release form
Core tablet Per tablet
Isoniazid 150 mg
Lactose 30 mg
Eudragit L 30 D (Rohm Pharma, Germany) 50 mg
Purified Water
Pass Isoniazid and Lactose through sieve and granulate with aqueous dispersion of diluted Eudragit L 30 D in a mass mixer for atleast 2 hours. Pass the granules through sieve and dry them.
Outer Tablet
Isoniazid Enteric Coated equivalent to 230 mg
Isoniazid 150 mg
Ethambutol Hydrochloride 400 mg
Pyrazinamide 750 mg
Rifampicin 225 mg
Lactose 20 mg
Magnesium Stearate 10 mg
Sodium Starch Glycollate 35 mg
Povidone 30 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin and Lactose through a sieve and granulate with Povidone solution in water. Pass the wet mass through multimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Mix Magnesium Stearate , Sodium Starch Glycollate and Isoniazid granules with above granules and compress.
Film Coating of tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
22. Molecular dispersion of Isoniazid with enteric (delayed release) effect
Isonizid 10.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 2.00 Kg
Isopropyl Alcohol 5.0 L
Alcohol 15.0 L
Dissolve Eudragit L 100 in Isopropyl Alcohol. Dissolve Isoniazid in Alcohol and add to the above solution and mix for one hour. Evaporate the solvents on a water bath and pass the residue through a sieve of mesh size 100.
The above powder may be used to make capsules, tablets or oral suspension.
23. Molecular dispersion of Isoniazid with enteric (delayed release) effect
tsoniazid 8.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 1.00 Kg
Polyvinyl Acetate Phthalate 0.75 Kg
Isopropyl Alcohol 4.0 L
Alcohol 15.0 t
Dissolve Eudragit L 100 and Polyvinyl Acetate Phthalate in Isopropyl Alcohol separately. Mix both the solutions and dissolve Isoniazid in Alcohol and add to the above solution and mix for one hour. Evaporate the solvents on a water bath and pass the residue through a sieve of mesh size 100.
The above powder may be used to make capsules, tablets or oral suspension.
24. Molecular dispersion of Isoniazid with enteric (delayed release) effect
Isoniazid 2.00 Kg
Shellac 0.10 Kg
Isopropyl Alcohol 1.0 L
Alcohol 5.0 L
Dissolve Shellac in a Isopropyl Alcohol. Dissolve Isoniazid in Alcohol and add to the above solution and mix for two hours. Evaporate the solvents on a water bath and pass the residue through a sieve of mesh size 100.
An oral suspension using above molecular dispersion is described below: Oral Suspension
Isoniazid 150 mg
(In delayed release molecular dispersion form as per example 23)
Rifampicin 225 mg
Ethambutol Hydrochloride 400 mg
(in ion-exchange complexed form for taste
masking as per example 28)
Pyrazinamide 750 mg
Colloidal Silicon Dioxide 100 mg
Aspartame 20 mg
Flavour q.s
Medium Chain Triglyceride q.s to 10 ml
Disperse Colloidal Silicon Dioxide, Aspartame in Medium chain Triglyceride. Add
Isoniazid powder, Rifampicin, Ethambutol Hydrochloride and Pyrazinamide and
flavour with stirring.
25. Enteric Coated beads of Isoniazid
Isoniazid 1.0 Kg
Non-pareil beads 3.0 Kg
Polyvinyl Pyrrolidone 0.20 Kg
Isopropyl Alcohol 14.00 L
EudragitHOO 0.80 Kg
Acetone 12.00 L
Water . 2.00 L
Triethyl Citrate 0.10 Kg
Procedure
The enteric coated beads of Isoniazid are manufactured using fluid bed coater. Spray dispersion of Isoniazid and Polyvinyl Pyrrolidone in Isopropyl Alcohol onto the fluidized non pareil beads. Further coat dispersion of Eudragit L100 and Triethyi Citrate in water/Acetone mixture on the Isoniazid beads.
Such beads may be used in conjunction with other drug to make formulation as
exemplified below:
(i) Isoniazid 150 mg
(In enteric coated bead form as per example 15)
(ii) Rifampicin 600 mg
Mix (I) and (ii) and fill in hard gelatin capsules, or mix (I) and (ii) with suitable lubricants and diluent like lactose, microcrystalline cellulose and compress into tablets
26. Isoniazid in Lipophilic Matrix
Isoniazid 5.0 Kg
Glyceryl Monostearate 2.0 Kg
Poloxamer188 0.1 Kg
Lactose 2 Kg
Ethyl Cellulose 1.0 Kg
Alcohol 10.0 L
Dissolve Glyceryl Monostearate and Poloxamer in Alcohol and heat up to 70°C so as
to obtain a clear solution. Add drug to the bulk and cool. Evaporate the Alcohol and
granulate the mixture with Lactose as diluents and Ethyl Cellulose as binder.
The above mentioned granules of Isoniazid may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
27. Bilayer tablet containing Isoniazid in extended release form
Layer -1
Isoniazid 0.150 g
Hydroxypropylmethyl Cellulose K4M 0.050 g
Isopropyl Alcohol 2.000 g
Layer- II
Rifampicin 0.225 g
Ethambutol Hydrochloride 0.400 g
Pyrazinamide 0.750 g
Starch 0.075 g
Granulate Isoniazid with solution of Hydroxypropylmethyl Cellulose K4M in Isopropyl Alcohol and dry. Granulate Rifampicin, Ethambutol Hydrochloride and Pyrazinamide with Starch paste in water and dry. Compress into bilayered tablets on a rotapress. Rifampicin (Layer- II) is immediately released. Isoniazid layer is released in delayed form.
28. Ethambutol Hydrochloride in taste masked form using complexation
Ethambutol Hydrochloride 1.0 Kg
Polystyrene Copolymer 2.0 Kg
Water 5.0 L
Disperse Polystyrene copolymer in Water and add Ethambutol Hydrochloride to it with constant stirring. Continue stirring for two hours and filter the complex and dry.
The above complex may be included in a tablet, capsule or suspension dosage form for taste masked and delayed release Isoniazid suspension containing other antitubercuiar drugs.
29. Tablet-in-tablet formulation (Rifapentine in delayed release form)
Core tablet: Per tablet
Rifapentine 150 mg
Microcrystalline Cellulose 75 mg
Starch 10 mg
Water
Disodium Edetate 3 mg
Magnesium Stearate 5 mg
Purified Talc 2 mg
Sodium Lauryl Sulphate 5 mg
Pass Rifapentine and Microcrystalline Cellulose through sieve and granulate the mass with Starch paste and pass through multimill. Dry the granules at 50° to 60°C and pass through sieve of mesh size 18. Pass Magnesium Stearate, Disodium
Edetate, Sodium Lairryl Sulphate and Purified Talc through sieve of mesh size 60 and mix with the dried granules and compress.
Enteric Coating of Rifapentine Tablets (Batch Size 2.0 Kg)
Cellulose Acetate Phthlate 85.00 g
Purified Talc 20.00 g
Polyethylene Glycol 400 10.00 g
Dichloromethane 1.33 L
Isopropyl Alcohol 0.66 L
Dissolve Cellulose Acetate Phthlate in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400 and Talc to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 4 - 6% w/w.
Outer Tablet
Pyrazinamide 750 mg
Ethambutol Hydrochloride 400 mg
Isoniazid 150 mg
Lactose 60 mg
Magnesium Stearate 20 mg
Sodium Starch Glycollate 30 mg
Starch 20 mg
Purified Talc 5 mg
Purified Water
Pass Pyrazinamide, Ethambutoi Hydrochloride, Isoniaztd and Lactose through a sieve and granulate with Starch Paste prepared in Purified Water. Pass the wet mass through muttirnill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules. Compress the tablets alongwith the Rifapentine enteric coated tablets in between.
Film Coating of outer tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
30. Effervescent Tablet / granules (Rifampicin in delayed release form).
Per tablet
Rifampicin Enteric Coated Granules
Equivalent to Rifampicin (from example no. 8) 225 mg
Pyrazinamide 750 mg
Isoniazid 150 mg
Ethambutoi Hydrochloride 400 mg
Anhydrous Citric Acid 340 mg
Sodium Bicarbonate 360 mg
Anhydrous Sodium Carbonate 20 mg
Povidone 50 mg
Polyethylene Glycol 6000 25 mg
Sodium Benzoate 20 mg
Aspartame 20 mg
Magnesium Stearate 7.5 mg
Sodium Lauryl Sulphate 2.5 mg
Flavour 25 mg
Isopropyl Alcohol
Dichloromethane —
Pass Pyrazinamide, Ethambutoi Hydrochloride, Isoniazid through a sieve of mesh size 40. Pass Anhydrous Citric Acid, Sodium Bicarbonate and Anhydrous Sodium Carbonate through sieve of mesh size 100 and mix with the above bulk. Dissolve
Povidone in Isopropyl Alcohol and Dichloromethane mixture and granulate the bulk with binder solution and pass the wet mass through multimill and dry the granules. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Polyethylene Glycol 6000, Aspartame, Sodium Benzoate, Sodium Lauryl Sulphate and flavour through sieve and mix with dried granules.
The above effervescent granules can be dispensed in a pouch / satches or in a tablet dosage form. All the processing is carried in dehumidified conditions at relative humidity not more than 20% and temperature not more than 25°C.
31. Buffered tablets containing Rifampicin in delayed release form
Per tablet
Rifampicin 225 mg
Pyrazinamide 750 mg
Isoniazid 150 mg
Ethambutol Hydrochloride 400 mg
Lactose 22.5 mg
Starch 30 mg
Magnesium Stearate 7.5 mg
Sodium Starch Glycollate 30 mg
Sodium Carbonate ' 100 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid and Lactose through a sieve of mesh size 40. Granulate the above bulk with Starch paste containing water and pass the wet mass through multimili and dry the granules. Pass Magnesium Stearate, Sodium Starch Glycollate and Sodium Carbonate through sieve and mix with dried granules, rifampicin enteric coated granules and compress.
Film Coating of tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
32. Hard Gelatin Capsule Formulation Containing Isoniazid in Delayed
Release form.
Per Capsule
Isoniazid Enteric Coated tablets 100 mg
(example no. 20)
Pyrazinamide (Compacted) 250 mg
Ethambutol Hydrochloride (Compacted) 267 mg
Rifampicin (Compacted) 150 mg
Sodium Lauryl Sulphate 3 mg
Pass Pyrazinamide, Ethambuto! Hydrochloride , Rifampicin through sieve of mesh size 22 and mix with the Sodium Lauryl Sulphate previously passed through sieve of mesh size 40. Fill the above bulk in empty hard gelatin capsules size "00" with a Isoniazid enteric coated tablet.
33. Molecular dispersion of rifabutin with enteric (delayed release) effect
Rifabutin 10.00 Kg
Eudragit L100 (Rohm Pharma, Germany) 2.50 Kg
Isopropyl Alcohol 6.0 L
Dichloromethane 17.0 L
Dissolve Eudragit L 100 in a mixture of Isopropyl Alcohol and Dichloromethane.
Disslove Rifabutin in Dichloromethane and add to the above solution and mix for one
hour. Evaporate the solvents on a water bath and pass the residue through a sieve
of mesh size 100.
The above mentioned powder of Rifabutin may be blended with other anti-tubercular drugs and suitable excipients to formulate into tablets, capsules or suspension.
34. Tablet formulation containing Rifabutin in Delayed Release form
Per tablet
Rifabutin
(In delayed release molecular dispersion form 150 mg
as per example 33)
isoniazid 150 mg
Ethambutol Hydrochloride 400 mg
Pyrazinamide 750 mg
Lactose 135 mg
Magnesium Stearate 20 mg
Sodium Starch Glycollate 30 mg
Starch 30 mg
Purified Talc 5 mg
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid and Lactose through a sieve and granulate with Starch Paste prepared in Purified Water. Pass the wet mass through muitimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Mix Magnesium Stearate , Sodium Starch Glycollate: Purified Talc and Rifabutin delayed release powder with dried granules and compress.
Film Coating of tablets (Batch Size 2.0 Kg)
Hydroxypropyi Methylcellulose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hydrxypropylmethylcellulose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3-4%
w/w.
35. Powder for reconstitution containing Isoniazid in Delayed Release form.
Each 10 ml of reconstituted suspension contains
Isoniazid
(In delayed released molecular dispersion form
as per example 22) 150 mg
Rifampicin 225 mg
Ethambutol Hydrochloride 400 mg
(In ion exchange complexed form for taste
masking as per example 28)
Pyrazinamide 750 mg
Methyl Hydroxybenzoate 5 mg
Sodium Metabisulphite 10 mg
Sweetening Agent q.s.
Xanthan Gum 20 mg
Flavour q.s.
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid delayed release powder, Rifampicin, Methyl Hydroxybenzoate, and Sodium Metabisulphite through sieve of mesh size 60. Pass Xanthan Gum and Sweetening Agent through a sieve of mesh size 100. Mix both the bulks and fill in amber coloured glass bottles.
38. Powder for reconstitution containing Rifampicin in Delayed Release form.
Each 10 ml of reconstituted suspension contains
Rifampicin
(in delayed release molecular dispersion
form as per example 9) 225 mg
Isoniazid 150 mg
(in taste masked form as per example 39)
Ethambutol Hydrochloride 400 mg
(In ion exchange comptexed form for taste masking
as per example 28)
Pyrazinamide 750 mg
Methyl Hydroxybenzoate 5 mg
Sodium Metabisulphite 10 mg
Sweetening Agent q.s.
XanthanGum 20 mg
Flavour q.s.
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid, Rifampicin delayed release powder, Methyl Hydroxybenzoate, and Sodium Metabisulphite through sieve of mesh size 60. Pass Xanthan gum and Sweetening Agent through a sieve of mesh size 100 and mix both the bulks and fill in amber coloured glass bottles.
37. An Anti Tubercular formulation in kit form.
The kit contains (A) One tablet of Isoniazid 150 mg (Enteric coated)
(B) One tablet containing Rifampicin, Ethambutol Hydrochloride and Pyrazinamide (Film coated)
(A) Isoniazid Tablets 150 mg (Enteric coated)
Per tablet
Isoniazid 150 mg
Lactose 30 mg
Starch 5 mg
Water
Magnesium Stearate 3 mg
Purified Talc 3 mg
Pass Isoniazid and Lactose through sieve and granulate the mass with Starch paste and pass through multimill. Dry the granules at 50° to 60°C and pass through sieve
of mesh size 18. Pass Magnesium Stearate and Talc through sieve of mesh size 60 and mix with the dried granules and compress.
Enteric Coating of Isoniazid Tablets (Batch Size 2.0 Kg)
Eudragit L 100 80.00 g
Purified Talc 25.00 g
Triethyl Citrate 15.00 g
Dichloromethane 1.30 L
Isopropyl Alcohol 0.60 L
Dissolve Eudragit L 100 in Isopropyl Alcohol and Dichloromethane mixture. Add Triethyl Citrate and Talc to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 4 - 6% w/w.
(B) Rifampicin, Ethambutol Hydrochloride and Pyrazinamide Tablets (film coated)
Per Tablet
Pyrazinamide 750 mg
Ethambutol Hydrochioride 400 mg
Rifampicin 225 mg
Lactose 50 mg
Magnesium Stearate 15 mg
Talc 6 mg
Starch 19 mg
Crospovidone 35 mg
Purified Water
Pass Pyrazinamide. Ethambutol Hydrochloride, Rifampicin and Lactose through a sieve and granulate with Starch paste prepared in Purified Water. Pass the wet mass through multimill and dry the granules at 50 - 60° C. Pass dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Crospovidone through sieve of mesh size 60 and mix with dried granules and compress.
Film Coating of tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
38. An Antl Tubercular formulation in kit form.
The kit contains (A) One tablet of R'rfampicin 150 mg (Enteric coated).
(B) One tablet containing Isoniazid, Etnambutol Hydrochloride and Pyrazinamide (Film coated).
(A) Rifampicin Tablets 150 mg (Enteric coated)
Per tablet
Rifampicin 225 mg
Microcrystalline CeHulose 55 mg
Starch 10 mg
Water
Magnesium Stearate 5 mg
Sodium Laury! Sulphate 5 mg
Pass Rifampicin and Microcrystalline Cellulose through sieve and granulate the mass with Starch paste and pass through multimili. Dry the granules at 50° to 60°C and pass through sieve of mesh size 18. Pass Magnesium Stearate and Sodium Lauryl Sulphate through sieve of mesh size 60 and mix with the dried granules and
compress.
Enteric Coating of Rifampicin Tablets (Batch Size 2.0 Kg)
Eudragit L 100 80.00 g
Purified Talc 25.00 g
Triethyl Citrate 15.00 g
Dichloromethane 1.30 L
Isopropyl Alcohol 0.60 L
Dissolve Eudragit L 100 in a Isopropyl Alcohol and Dichloromethane mixture. Add Triethyl Citrate and Talc to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 4 - 6% w/w.
(B) Isoniazid, Ethambutol Hydrochloride and Pyrazinamide Tablets (film coated)
Per Tablet
Pyrazinamide 750 mg
Ethambutol Hydrochloride 400 mg
Isoniazid 150 mg
Magnesium Stearate 15 mg
Talc 6 mg
Starch 35 mg
Sodium Starch Glycollate 35 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride and Isoniazid through a sieve and granulate with Starch paste prepared in Purified Water. Pass the wet mass was passed through multimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules and compress.
Film Coating of tablets (Batch Size 2.0 Kg)
Hydroxypropyl Methylcellulose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour . q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hydroxypropyl Methylcellulose in Isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 4CX), Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3-4% w/w.
39. Isoniazid in taste masked form using complexation
Isoniazid 1.0 Kg
Polystyrene Copolymer 2.0 Kg
Water 5.0 L
Disperse Polystyrene copolymer in Water and add Isortazid to it with constant stirring. Continue stirring for two hours and filter the complex and dry.
The above complex may be included in a tablet, capsule or suspension dosage form for taste masked and delayed release Isoniazid suspension containing other antitubercular drugs.
40. Microemulsion formulation of Rifamptein and other Tubercular drugs.
Per Tablet
Rifampicin 150 mg
Pyrazinamide 250 mg
Ethambutol Hydrochloride 267 mg
Isoniazid 100 mg
Poloxamer 188 25 mg
Vitamin E Polyethylene Glycol Succinate 20 mg
Hydrogenated Oil 20 mg
Magnesium Stearate 15 mg
Talc 6 mg
Starch 35 mg
Sodium Starch Glycollate 35 mg
Purified Water —
Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin and Isoniazid through a sieve and granulate with Starch paste containing Poloxamer 188, Poloxamer 407 and Hydrogenated oil. Pass the wet mass was passed through multimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules and compress.
Such tablets on dilution with water gives a microemulsion. 41. Vesicular carriers for Rifampicin
Rifampicin 500 mg
Chloroform q.s.
Cholesterol 49 mg
Polysorbate 80 35 mg
Distearyl Phosphatidyl Choline 7 mg
Dichloromethane 10 ml
Calcium Chloride (25mM ssolution) 10 ml
Dissolve Rifampicin in minimum volume of Chloroform and add Cholesterol, Polysorbate 80 and Distearyl Phosphatidyl Choline to it. Add Dichloromethane, 2ml of calcium Chloride solution. Sonicate for 2 hours or till a milky emulsion is formed and evaporate the solvent layer under controlled conditions of temperature and pressure on a rota evaporator till a semisolid viscous liquid is obtained. Now add remaining amount of Calcium Chloride solution and evaporate the solvents on a rota evaporator for overnight and collect the vesicular carriers.
Such carriers can be incorporated into a tablet, capsule or liquid dosage form.
42. Tablet containing Rifampicin in molecular dispersion (in delayed release) form.
Per Tablet Rifampicin (In delayed release molecular dispersion form
as per example no. 9) 225 mg
Pyrazinamide 750 mg
Ethambutol Hydrochloride 400 mg
Isoniazid 150 mg
Lactose 60 mg
Magnesium Stearate 20 mg
Sodium Starch Glycollate 30 mg
Starch 20 mg
Purified Talc 5 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride, Isoniazid and Lactose through a sieve and granulate with Starch Paste prepared in Purified Water. Pass the wet mass through multimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules and rifampicin delayed release powder. Compress the blend into tablets.
Film Coating of tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
Isopropyl Alcohol 0.33 L
Dissolve Hypromellose in isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight buiW up of 3 - 4% w/w.
43. Tablet containing Isoniazid in molecular dispersion (in delayed release) form.
Per Tablet
Isoniazid
(in delayed release molecular dispersion form
as per example no. 23) 150 mg
Pyrazinamide 750 mg
Ethambutol Hydrochloride 400 mg
Rifampicin 225 mg
Lactose 60 mg
Magnesium Stearate 20 mg
Sodium Starch Glycollate 30 mg
Starch 20 mg
Purified Talc 5 mg
Purified Water
Pass Pyrazinamide, Ethambutol Hydrochloride, Rifampicin and Lactose through a sieve and granulate with Starch Paste prepared in Purified Water. Pass the wet mass through multimill and dry the granules at 50 - 60° C. Pass the dried granules through sieve of mesh size 16. Pass Magnesium Stearate, Purified Talc and Sodium Starch Glycollate through sieve of mesh size 60 and mix with dried granules and isoniazid delayed release powder. Compress the blend into tablets.
Film Coating of tablets (Batch Size 2.0 Kg)
Hypromellose 40.00 g
Purified Talc 2.00 g
Polyethylene Glycol 400 8.00 g
Titanium Dioxide 2.00 g
Colour q.s.
Dichloromethane 0.66 L
isopropyl Alcohol 0.33 L
Dissolve Hypromellose in isopropyl Alcohol and Dichloromethane mixture. Add Polyethylene Glycol 400, Titanium Dioxide, Purified Talc and colour to the above bulk and mix for 45 minutes. Coat the tablets to a weight build up of 3 - 4% w/w.
















We Claim :
1. A process for the preparation of a pharmaceutical
composition of anti-tubercular drugs for oral use comprising
Rifampicin and Isoniazid in delayed release form or extended
release form characterised in that Rifampicin and/or
Isoniazid is treated with pH sensitive or pH independent
polymers, as herein described, by conventional techniques
whereby the bioavailability of Rifampicin is enhanced by
preventing its degradation caused by presence of Isoniazid
amd optionally adding conventional buffers and bio-avail
ability enhancing agents to the composition prepared.
2. The process as claimed in claim 1 wherein Rifampicin is in
delayed release or extended release form.
3. The process as claimed in claim 1 wherein Isoniazid is in
delayed release or extended release form.
4. The process as claimed in claim 1 wherein the polymer used
is a pH sensitive polymer selected from the group comprising
Cellulose acetate phthalate, Hydroxypropyl methylcellulose
phthalate, Polyvinyl acetate phthalate, Hydroxypropyl methyl
cellulose acid succinate, Methacrylic acid Polymers,
Polacrillin potassium and Chitosan.
5. The process as claimed in claim 1 wherein the polymer used
is a pH independent polymer selected from the group
comprising Cellulose derivatives, Hydroxypropyl methyl
cellulose, Hydroxypropyl cellulose, Hydroxyethyl cellulose, Ethyl cellulose, Natural gums - Xanthan gum, Karaya gum, and Tragacanth.
6. The process as claimed in claims 1 to 5 wherein the drugs
Rifampicin and/or Isoniazid are present in micronized form.
7. The process as claimed in claims 1 to 6 wherein the drugs
Rifampicin and/or Isoniazid are present in taste neutralized
form.
8. The process as claimed in claims 1 to 7 wherein crystal or
polymorphic forms of Rifampicin and/or Isoniazid having
reduced solubility between pH 1 and 4 are used.
9. The process as claimed in any of the proceeding claims
wherein conventional buffers are added to the composition
to raise the pH of gastric contents beyond 3.
10. The process as claimed in any of the proceeding claims
wherein conventional bioavailability enhancing agents -
Piperine and Ayurvedic formulation Trikatu are added to the
composition.
11. The process as claimed in any of the proceeding claims
wherein the composition prepared is formed into tablets,
capsules, suspensions,pastilles or jellies by known methods.
12. The process for the preparation of anti- tubercular composition for oral use substantially as herein described and illustrated by the examoles herein.

Documents:

721-del-2000-abstract.pdf

721-del-2000-claims.pdf

721-del-2000-complete specification (granted).pdf

721-del-2000-correspondence-others.pdf

721-del-2000-correspondence-po.pdf

721-del-2000-description (complete).pdf

721-DEL-2000-Description (Provisional).pdf

721-del-2000-form-1.pdf

721-DEL-2000-Form-2.pdf

721-del-2000-form-3.pdf

721-del-2000-form-4.pdf

721-del-2000-form-5.pdf

721-del-2000-gpa.pdf

721-del-2000-petition-138.pdf


Patent Number 240046
Indian Patent Application Number 721/DEL/2000
PG Journal Number 30/04/2010
Publication Date 30-Apr-2010
Grant Date 26-Apr-2010
Date of Filing 09-Aug-2000
Name of Patentee PANACEA BIOTEC LIMITED
Applicant Address B-1 EXT. / A-27, MOHAN CO-OPERATIVE INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044
Inventors:
# Inventor's Name Inventor's Address
1 DR. AMARJEET SINGH PANACEA BIOTEC LIMITED,B-1 EXT. / A-27, MOHAN CO-OP. INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044
2 JAIN RAJESH DIRECTOR,PANACEA BIOTEC LIMITED,B-1 EXT. / A-27, MOHAN CO-OP. INDUSTRIAL ESTATE, MATHURA ROAD, NEW DELHI-110044
PCT International Classification Number A61K 31/496
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA