ZA200309212B

ZA200309212B - An improved process for preparation of four-drug anti-tubercular fixed dose combination.

Info

Publication number: ZA200309212B
Application number: ZA200309212A
Authority: ZA
Inventors: Sen Himadri; Kishor Dattatray Deo; Kour Chand Jindal; Krishnakant Tulsiram Gandhi
Original assignee: Lupin Ltd
Priority date: 2003-11-26
Filing date: 2003-11-26
Publication date: 2004-11-24

Description

An improved process for preparation of four-drug anti-tubercular fixed dose combination

Field of Invention

The invention relates to an improved process for preparation of a composition comprising fixed dose combination (FDC) of four anti-tubercular drugs viz. rifampicin, isomazid, pyrazinamide and ethambutol hydrochloride, which improves the dissolution of poorly soluble drug rifampicin and hence improve its bioavailability. The invention further relates to an improved process for preparation of a composition comprising fixed dose combination (FDC) of four anti-tubercular drugs viz. rifampicin, isomazid, pyrazinamide and ethambutol hydrochloride, which improves the dissolution of poorly soluble drug rifampicin and hence improve its bioavailability, without use of a surfactant.

Background of Invention

One-third of the world’s population is infected with the tuberculosis bacillus. Currently there are 16 million patients with active disease and some 8 million new cases added each year with nearly 2 million annual deaths, including over one quarter of avoidable deaths among young adults worldwide. Developing countries account for an overwhelming burden of global TB problem, with 95% of TB cases and 98% of TB deaths.

Approximately 50 % of the India’s population is reported to be tuberculin test positive.

Every year about 0.4 million deaths and one million new cases of tuberculosis are reported (Tuberculosis Research Centre Bulletin, Madras, Vol. 1(2), April 1994). In short, tuberculosis remains a major health problem in India.

The reasons for the increase in the number of tuberculosis cases are probably due to: 1) Growing epidemic of HIV infection. i1) Malnutrition leading to reduced immunity. 1) Use of indiscriminate and inadequate chemotherapy iv) Multi-drug resistance due to partial adherence to chemotherapy. v) Inadequate bioavailability from poorly formulated pharmaceutical dosage forms.

The failure of anti-tubercular therapy is essentially due to non-compliance or partial compliance with the recommended therapy (Tubercle and Lung Disease, 74, 32, 1993).

It has been found that partial adherence to therapy is a grave menace to community because the patient who does not take any therapy at all, transmits non-resistant tubercle bacilli to others, whereas the patient, who takes partial therapy develops multi-drug resistance and transmits drug-resistant tubercle bacilli.

Emergence of drug resistance in high burden areas of the world presents a major threat to the future success of TB control. Drug resistance in most tuberculosis patients predominantly arises as a result of multiple interruptions of treatment. When using single drug formulations, patients are more prone to interrupt their treatment on some drugs while not on others, thereby creating a risk of monotherapy and selection of drug-resistant mutants. Furthermore, out-of-stock of expiry situations in treatment facilities, which might lead to some drugs being continued in isolation while new stocks of others are

I5 being awaited, represent another potential source of monotherapy. Such problems are prevented more easily if fixed dose combinations (FDCs) are used.

In order to control re-emergence of drug resistant tuberculosis, World Health

Organization (WHO) put forward a number of guidelines for effective treatment of tuberculosis, which include the following: “Directly Observed Therapy” (DOT) which requires complete supervision (Weis S. E. et. al., New Engl. J. Med., 330, 1179, 1994). “Automated Telephone Reminders” for appointments in a public health TB clinic (Tanke

E. D. and Leirer V. O., Med. Care, 32, 380, 1994),

Use of “Blister Calendar Packs” (Valeza F. S. and McDougall A. C., Lancet, 335, 473, 1990). “Short Course Chemotherapy” (SCC) comprises of two phases, with emphasis on simplicity and applicability. The initial phase consists of four drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol! hydrochloride given daily for two months and the second or continuation phase consists of two drugs viz. isoniazid and rifampicin given daily or intermittently. However, it was observed that in developing countries even with short course chemotherapy, cure rate did not reach even 85%.

Although, significant improvement in therapy compliance has been observed because of these concepts, some inherent disadvantages such as high supervisory cost, non- practicability in rural areas and selective discontinuation of some medications are associated with these approaches. Thus, to improve patient compliance, minimize drug resistance and for the ease of administration, the use of fixed dose combination has been recommended by World Health Organization (WHO), Center for Disease Control (CDC),

International Union Against Tuberculosis and Lung Disease (IUATLD) and, American

Thoracic Society [Statement of IUATLD and WHO in ‘Tubercle and Lung Disease’ 75, 180, 1994; Moulding T. et. al., Ann. Intern. Med, 122. 951,1995]. Tuberculosis needs the treatment with three to five different drugs simultaneously, depending upon the patient category. These anti-tuberculosis drugs can be given as single drug formulations or as fixed dose combinations (FDCs) where two or more anti-tuberculosis drugs are present in fixed proportions in the same formulation. WHO and IUATLD advocate the replacement of single drug preparations by FDC tablets as the primary treatment for tuberculosis.

FDCs have the following advantages: - They provide a simple approach to delivering the correct number of drugs at the correct dosage as all the drugs are combined in 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 the dose. - They provide better compliance to treatment regimen and effective therapy conveniently. - Monotherapy is prevented, consecutively the risk for drug resistant bacilli 1s reduced. - Prescription and administration is simplified; and doctor/patient compliance with regimen improved. - Better drug stock management, shipping, and distribution

The risk of misuse of rifampicin for conditions other than tuberculosis is reduced.

However, these medications are only effective if the individual components are available intissue at the correct concentration. A number of studies have shown that, if formulation/processes are not adequately optimized, such preparations can have serious limitations and may risk the possibility of adverse treatment results and the development of drug resistance. Ensuring a reliable quality medications is one of the corner stones of tuberculosis control, the major concern in using FDCs is quality because the use of sub- | standard FDCs may result in treatment failure and the emergence of drug resistance.

The major quality issue with FDC tablets is assuring the bioavailability of rifampicin. It is known that when rifampicin is combined with other drugs in the same formulation. its bioavailability is negatively affected if formulation/processes are not optimized and quality of active drugs is not controlled.

In a symposium on quality control of anti-TB drugs, at annual meeting of IUATLD in

Dubrovnik in 1988, Acocella (University of Pavia, Italy) presented studies on bioavailability of rifampicin in two and three-drug FDC tablets (Acocella G., Bull. Int.

Union Tuberc. Lung Dis., 64, 38, 1989). His work showed that the bioavailability of rifampicin when given as FDC tablets, particularly the three-drug combination, could be poor. Furthermore, an apparently satisfactory in-vitro dissolution test does not guarantee acceptable rifampicin bioavailability. The results of a series of studies have shown that while some FDC formulations had acceptable rifampicin bioavailability, others did not.

Giving FDC tablets with poor rifampicin bioavailability means giving inadequate therapy, without even being aware of it. Consequently, using FDC tablets of poor rifampicin bioavailability could directly lead to poor treatment outcome and may create, and not prevent, drug resistance. Good quality FDC tablets with demonstrated bioavailability of rifampicin, is an absolute requirement for successful treatment outcomes in programmes utilizing FDC-based regimens.

Bioavailability problems with the isomazid, pyrazinamide and ethambutol components of FDC tablets have not been encountered, presumably because of their much greater water-solubilities. It is assumed that impaired bioavailability may result from changes in rifampicin’s crystalline form during the tabletting process. 5

Besides being poorly soluble in water, the absorption of rifampicin is adversely affected by food. Rifampicin alone, in solid state, 1s stable but its stability in the presence of moisture and other anti-tubercular drugs together is questionable. Rifampicin is incompatible with isoniazid in presence of water (Ved S. and Deshpande S. G., Eastern

Pharmacist, 139, July 1990). Ethambutol hydrochloride, which is a highly hygroscopic material, tends to catalyze rifampicin and isoniazid interaction. Hence the development of four-drug FDCs containing rifampicin demands not only improving the solubility of rifampicin but also protecting it against oxidation and interaction with the other drugs.

The two, three and four-drug FDCs recommended by WHO and included in the WHO model list of essential drugs contain varying compositions of each drug based on the age, gender and weight of the patients they are intended for. To ensure that the process used for manufacturing the entire range of FDCs with variable active ingredient compositions is economically viable, a flexible process by means of which all the different compositions can be manufactured must be available.

Japanese Patent No. 53-133624 discloses a formula for overcoming poor elution properties of solid pharmaceutical preparations containing rifampicin. Capsules containing mixtures of rifampicin with crystalline cellulose alone or with crystalline cellulose together with polyethyleneglycol 40 monostearate, polyethyleneglycol 80 sorbitan monooleate, glycerol monostearate, hydroxypropy! cellulose or hydroxypropyl methylcellulose and magnesium stearate showed satisfactory elution properties when tested in a medium with a pH of 1.5 or 3, using the rotating basket method.

United States Patent No. 4,613,496 teaches that while the compositions described in the above Japanese patent show a considerable improvement of elution properties over those of ordinary preparations, it has been found that these properties are no longer satisfactory under neutral to slightly basic conditions when the elution rates are determined with the column dissolution rate testing method which more accurately reflects the actual physiological conditions prevailing in the human body than the rotating

S basket method.

United States Patent No. 4,613,496 discloses capsules containing a mixture of rifampicin, crystalline cellulose, sodium lauryl! sulfate and magnesium stearate, which show consistently more uniform and more complete dissolution rates using the column method than those of the compositions disclosed in the above Japanese patent.

United States Patent No. 5,104,875 discloses combination preparations containing rifampicin and thioacetazon and optionally isonicotinic acid hydrazide or ethambutol and its use for the treatment of mycobacterial infections.

United States Patent No. 6,107,276 discloses a technique for improving the dissolution of slightly soluble drugs by employing a water-swellable, but water-insoluble cross-linked polymer, a surface-active agent and an oil mixed with the drug for improving its bioavailability.

European Patent EP 330284 BI discloses a wet granulation process for making good quality granulate comprising of a drug present in high concentration but having limited solubility in water of less than 10 wt %, 20 —100 wt % of microcrystalline cellulose or microfine cellulose or a mixture of both and 0-0.5 wt % of a wet granulation binding substance. These granulates can be processed to solid tablets having a satisfactory disintegration behaviour. The text on page 4, lines 26-30, further elaborates the limitation of the invention, that the use of a wet granulation binding substance in the granulation mixture should be avoided or at least restricted to an amount of not more than 0.5 wt %, preferably to less than 0.1 wt % based on the weight of the drug. Otherwise the disintegration behaviour of the tablets prepared from these granulates is adversely affected.

PCT patent application WO 98/06382 discloses a granulate consisting of water soluble active ingredient at least 75 wt %, up to and including 100 wt % of a microcrystalline cellulose, and up to and including 0.5 wt % of a wet granulation binding agent prepared at room temperature by a wet granulation technique.

The Indian Patent No. 181730 discloses a wet granulation process for manufacture of tablets containing rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride along with pharmaceutically acceptable excipients, stabilizers and non-ionic surfactants.

This four-drug FDC is claimed to exhibit stability and bioavailability, which is comparable with single drug dosage forms containing equivalent amount of the drugs.

Two processes are described for manufacture of four-drug FDCs. In one process, rifampicin and ethambutol hydrochloride are to be wet granulated with excipients and isoniazid and pyrazinamide wet granulated with excipients followed by mixing and compression of granules obtained in these two steps. The other process teaches wet granulating rifampicin separately with excipients and the other 3 drugs together with excipients, mixing and compression of granules obtained in these two steps. These processes are hereinafter referred to as 2-step granulation processes. The disadvantages of the processes described lie in the fact that since 2 or more ingredients are granulated together, it is not possible to use the same granules to manufacture other FDCs having different strengths of the drugs.

As evident from the prior art, it becomes challenging to formulate a composition containing granules of water soluble drugs like ethambutol hydrochloride and isoniazid as well as of drugs having poor water solubility like rifampicin and pyrazinamide and still get a composition having good disintegration time. Such a composition when formulated

In a proper way can have acceptable disintegration time and show better dissolution profile for a drug like rifampicin leading to increased bioavailability.

There are three known principle methods for tabletting viz. direct compression, dry granulation and wet granulation. The direct compression method is not suitable for the four drug FDC as the actives have a very poor flow thus leading to processing problems during compression. The dry granulation method 1s also not advisable due to hygroscopic nature of ethambutol hydrochloride, which leads to heavy sticking on the rollers of compactor during compaction. The wet granulation method is the most preferred method as it leads to uniform particle size distribution, homogeneous mixture with free flowing properties and better compressibility.

The four drugs viz. rifampicin, isoniazid, pyrazinamide and ethambuto! hydrochloride cannot be granulated together in a single step wet granulation process because rifampicin is incompatible with isoniazid in presence of moisture. As discussed above, Indian Patent

No. 181730 teaches a 2-step wet granulation process for preparation of four-drug antitubercular FDC composition. Now, we have found that when all the four-drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol are granulated by a wet granulation process that is a 3-step or a 4-step process, surprisingly, the bioavailability of rifampicin is improved as compared to the 2-step granulation process patented earlier.

According to the present invention, in the 3-step process, rifampicin is granulated separately, isoniazid and pyrazinamide together and ethambutol hydrochloride is granulated separately.

According to the present invention, in the 4-step process, all the four-drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride are granulated separately.

Fixed dose combinations of rifampicin with isomazid (two-drug FDC) or with pyrazinamide and isoniazid (three-drug FDC) are commercially available. The four-drug

FDCs are also available, however, the major quality issue with these dosage forms is assuring the bioavailability of rifampicin. It is known that, when rifampicin is combined 5S with other drugs in the FDCs, its bioavailability is negatively affected, if the manufacturing formulations and processes are not optimized. This becomes more critical for development of a four-drug fixed dose combination containing rifampicin.

Surfactants are used as wetting agents to improve dissolution of poorly soluble drugs. The surfactants which can be used for this include anionic surfactants such as sodium lauryl sulfate (SLS), docusate sodium (dioctyl sodium sulfosuccinate) or non-ionic surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80.

Surprisingly we have found that addition of surfactant like sodium lauryl sulfate had a negative effect on the in-vitro release of rifampicin and on its bioavailability.

The object of the present invention is to provide an improved process for the preparation of stable and bioavailable anti-tubercular pharmaceutical composition of fixed dose combination of all four first line anti-tubercular drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride using a wet granulation manufacturing : process.

The further object of the invention is to provide an improved process for the preparation of stable and bioavailable anti-tubercular pharmaceutical composition of fixed dose combination of all four first line anti-tubercular drugs viz. nfampicin, isoniazid, pyrazinamide and ethambutol hydrochloride using a wet granulation manufacturing process wherein rifampicin bioavailability is not adversely affected.

One more object of the invention is to provide an improved process for the preparation of stable and bioavailable anti-tubercular pharmaceutical composition of fixed dose combination of all four first line anti-tubercular drugs viz. nfampicin, isoniazid,

pyrazinamide and ethambutol hydrochloride using a wet granulation manufacturing process, which does not involve use of a surfactant.

Another object of the present invention is to provide an improved process for the preparation of stable and bioavailable anti-tubercular pharmaceutical composition of fixed dose combination of all four first line anti-tubercular drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride using a wet granulation manufacturing process wherein rifampicin is protected against interaction with other drugs present in the composition.

Yet another object of the present invention is to provide an improved process for the preparation of stable and bioavailable anti-tubercular pharmaceutical composition of fixed dose combination of all four first line anti-tubercular drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride using a wet granulation manufacturing process to formulate varying strengths of the said drugs in fixed dose combination composition.

Summary of the Invention

According to an aspect of the present invention, there is provided an improved process for the preparation of an antitubercular pharmaceutical composition in fixed dose combination containing four drugs rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride comprising; a) mixing rifampicin with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; b) mixing isoniazid with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying;

c) mixing pyrazinamide with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; d) mixing ethambutol hydrochloride with excipients followed by wet granulation of resulting mixture with a binder matenal to obtain granules of said mixture and thereafter subjecting the said granules to drying; e) mixing the granules obtained in steps a), b), c) and d) with excipients to obtain a lubricated blend f) converting the resulting lubricated blend into a solid dosage form. oo

According to another aspect of the present invention, there is provided an improved process for the preparation of an antitubercular pharmaceutical composition in fixed dose combination containing four drugs rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride comprising; a) mixing rifampicin with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; b) mixing isoniazid and pyrazinamide with excipients followed by wet granulation of resulting mixture with a binder matenal to obtain granules of said mixture and thereafter subjecting the said granules to drying; c) mixing ethambutol hydrochloride with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; d) mixing the granules obtained in steps a), b) and ¢) with excipients to obtain a lubricated blend e) converting the resulting lubricated blend into a solid dosage form.

Brief description of the drawings

Figure 1 is a graph illustrating the dissolution profile of rifampicin from compositions prepared using 2-step, 3-step and 4-step granulation without use of a surfactant.

Figure 2 1s a graph illustrating the dissolution profile of rifampicin trom compasition with and without surfactant, sodium lauryl sulfate (SLS) prepared by a 3-step granulation process.

S Figure 3 is a graph illustrating the comparative release of rifampicin in-vivo over time for compositions prepared by 2-step and 3-step granulation process.

Detail description of invention

The invention relates to an improved process for preparation of a composition comprising fixed dose combination (FDC) of four anti-tubercular drugs viz. rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride which improves the dissolution of poorly soluble drug rifampicin and hence improve its bioavailability without the use of surfactants.

According to one aspect of the present invention, the four anti-TB drugs are granulated using a 3-step wet granulation process wherein rifampicin is granulated separately, isoniazid and pyrazinamide are granulated together and ethambutol is granulated separately.

According to another aspect of the present invention the four anti-TB drugs are granulated using a 4-step wet granulation process, wherein rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride are granulated separately.

According to the present invention the 4-step granulation process, comprises a) mixing rifampicin with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; b) mixing isoniazid with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafier subjecting the said granules to drying;

] c) mixing pyrazinamide with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter . subjecting the said granules to drying; d) mixing ethambutol hydrochloride with excipients followed by wet granulation of

S resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; e) mixing the granules obtained in steps a), b), ¢) and d) with excipients to obtain a lubricated blend f) converting the resulting lubricated blend into a solid dosage form.

According to the present invention the 3-step granulation process, comprises a) mixing rifampicin with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; ) b) mixing isoniazid and pyrazinamide with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; c) mixing ethambutol hydrochloride with excipients followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; d) mixing the granules obtained in steps a), b) and c) with excipients to obtain a lubricated blend e) converting the resulting lubricated blend into a solid dosage form.

The solid dosage forms obtained according to the process of present invention may be tablets or capsules or granules. The tablets may be obtained by compression of the resultant granules after lubrication and the compressed tablets may be film coated. But . when capsules are chosen as the dosage form the granules can be used as such or granules can be used to prepare a suspension.

The excipients, which can be used in the process of the present invention besides binder materials include one or more of antioxidants, inert diluents, disintegrants and conventional additives such as lubricating agents or coating agents but not surfactants. .

The inert diluents, which can be used in the process of the present invention include calcium carbonate, calcium sulfate, dextrates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, lactose, mannitol, microcrystalline cellulose, starch, polymethacrylates and the like. The preferred diluents are microcrystalline cellulose, lactose, dibasic calcium phosphate and starch.

The alkaline aqueous solution of rifampicin in presence of atmospheric oxygen oxidizes to rifampicin quinone at room temperature and into 25—desacetyl rifampicin and 25- desacetyl-23-acetyl rifampicin. Ascorbic acid slows down the oxidation of Rifampicin to tts oxidation products. In Acidic aqueous solution, rifampicin converts to 3-formyl

I5 rifampicin SV and is formed by reversible cleavage (Analytical profile of drug substances, Ed. Klaus Florey, vol. 5, pg. 491-494, 1976 and references cited therein).

The antioxidants which can be used in the process of the present invention include sodium metabisulphite, sodium sulphite, a-tocopherol, ascorbic acid, sodium ascorbate, malic acid, propylgallate and the like. The preferred antioxidants are ascorbic acid and sodium ascorbate.

According to a preferred embodiment of the present invention antioxidant used is ascorbic acid in the range of 0.1 to 1.5 wt % of the total composition, preferably in the range of 0.1to | wt %.

The binder materials which can be used in the process of the present invention include gelatin, starch, povidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, i pregelatinized starch, sucrose, acacia, alginic acid, sodium alginate and the like. The preferred binder materials are pregelatinised starch, povidone and gelatin.

. The binder material or mixtures thereof may be present in the range of 1 to 20 wt % of the total composition, preferably in the range of 2 to 15 wt %.

Pregelatinised Starch is partially gelatinised starch. The binder solution prepared from a 5S partially gelatinised starch is much more consistent in binding properties as compared to fully gelatinised starch. The partially gelatinised starch has muiti-functional advantages, it is used as a binder, disintegrant, flow aid, lubricant, it also enhances formulation flexibility by complementing functionality of other excipients. It is known to facilitate the wetting, particularly of hydrophobic drugs and thus significantly affecting subsequent drug dissolution.

In a preferred embodiment of the present invention pregelatinised starch is used as a binder in the range of 1 to 15 wt % of the total composition, preferably in the range of 3 to 12 wt %.

In a more preferred embodiment of the present invention pregelatinized starch is used as a binder for granulation of poorly soluble drug rifampicin.

In another preferred embodiment of the present invention gelatin is used as a binder in the range of 0.2 to 2 wt % of the total composition, preferably in the range of 0.3 to | wt %.

In yet another preferred embodiment of the present invention povidone is used as a binder in the range of 0.2 to 5 wt % of the total composition, preferably in the range ot’ 0.3 to 4 wt %. . The lubricating agents, which can be used in the process of the present invention include magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, hydrogenated . vegetable oil and the like. The preferred lubricating agents are colloidal silicon dioxide and magnesium stearate.

The disintegrants, which can be used in the process of the present invention include crospovidone, sodium starch glycollate, croscarmellose sodium, microcrystalline cellulose and the like. The preferred disintegrants are crospovidone and sodium starch glycollate.

Crospovidone is added in rifampicin granulation and at lubrication stage before compression. It helps in reducing the disintegration time and thereby improves dissolution of rifampicin. Crospovidone provides porous capillary network for penetration of water and thus reduces disintegration time of the composition.

According 10 a preferred embodiment of the present invention disintegrant used is crospovidone in the range of 1 to 10 wi % of the total composition, preferably it is in the range of 2 to 8 wt %.

I5 The granules obtained by wet granulation with a binder material are dried at a temperature between 40° C to 80° C, preferably between 50° C to 70° C.

The coating agents which can be used in the process of the present invention include hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic acid copolymers, cellulose acetate phthalate, cetyl alcohol, shellac, microcrystalline wax,

Opadry AMB and the like. The preferred coating agent is Opadry AMB.

Figure 1 shows the result obtained when all the three compositions i.e. by 2-step granulation, 3-step granulation and 4-step granulation prepared without using a surfactant, were studied for in-vitro release. It was clearly evident that the 2-step granulation formulation was inferior compared to 3-step and 4-step granulation. The 3 and 4-step granulated compositions were comparable.

Four-drug FDC Compositions prepared according to the process of present invention, by 3-step or 4-step granulation shows better dissolution profile of rifampicin than when granulated by 2-step granulation process. This might be attributed to higher disintegration

~ time, when granulated by a 2-step granulation process. Ethambutol hydrochloride being ) a highly water soluble drug, when formulated alone into a tablet formulation, disintegrates by slow erosion instead of fragmentation. Hence ethambutol when granulated along with pyrazinamide and isoniazid affects the granule characteristics and disintegration time of the composition. When ethambutol was granulated separately, it was found that there was a significant improvement in disintegration time, which was further improved by a 4-step granulation process where all four-drugs were individually granulated. The advantage of 4-step granulation process apart from improving the dissolution which in turn improves the bioavailability of rifampicin, is the flexibility of formulating different strengths of fixed dose combination compositions, which is very : essential for treatment of tuberculosis, wherein the treatment varies depending on the weight/age of the patient and severity of infection.

To study the effect of a surfactant on the compositions prepared according to the process of the invention, in-vitro dissolution of rifampicin from compositions with and without sodium lauryl sulfate (SLS), prepared by using a 3-step granulation process were studied.

Figure 2 shows comparative dissolution of rifampicin from compositions with and without SLS, prepared according to 3-step granulation process of the present invention.

Use of a surfactant like SLS affected the in-vitro dissolution of rifampicin adversely. The composition without SLS showed better in-vitro dissolution for rifampicin.

When we compared bioavailability of rifampicin in four-drug FDC manufactured by 3- step and 2-step granulation processes without using a surfactant, the plasma blood levels of rifampicin from the four-drug FDC, manufactured by 3-step granulation process were 25. found to be higher than the 2-step granulation process. Two-treatment, two-period, two- sequence, single dose cross over in-vivo study was performed on minimum 12 healthy ) adult human subjects under fasting condition. Figure 3 shows comparative rifampicin bioavailability in-vivo from composition prepared according to 3-step granulation of the ’ present invention and 2-step granulation. It is evident that composition manufactured by employing 3-step granulation process shows improved rifampicin bioavailability.

It is particularly preferred for the composition to exist in a form suitable for oral administration, i.e. as tablets or capsules. Such dosage units preferably contain 60 to 600 mg rifampicin, 100 to 1000 mg ethambutol hydrochloride, 30 to 300 mg isoniazid and 150 to 1200 mg pyrazinamide.

The invention is further illustrated by the following examples, which should however not be construed as a limitation of the invention.

EXAMPLES

A) 3-Step Granulation Process Rifampicin, microcrystalline cellulose or lactose, crospovidone and pregelatinized starch or povidone were mixed. Ascorbic acid was dissolved in water and then pregelatinized starch dispersed in water or povidone (polyvinyl pyrrolidone K-30) was dissolved in water to make a binder solution. The blend was granulated with the binder solution.

Isomazid, pyrazinamide, microcrystalline cellulose or lactose were mixed. The blend was granulated with pregelatinized starch dispersed in water or povidone (polyvinyl pyrrolidone K-30) dissolved in water.

Ethambutol hydrochloride and microcrystalline cellulose or dicalcium phosphate were

I5 mixed and granulated with gelatin solution. After drying, the granules of all 3-steps were blended together and mixed with silicon dioxide, microcrystalline cellulose, crospovidone or sodium starch glycollate and magnesium stearate. The granules were compressed into tablets and coated with Opadry AMB Brown, which is a readymade coating composition manufactured by Colorcon Asia Ltd., India; which consists of polyvinyl alcohol, titanium dioxide, talc, lecithin, xanthan gum and iron oxide colorant.

The tablets were tested for rifampicin release at 10, 20, 30 and 45 minutes in 900 ml.of 0.1 N HCl using USP Apparatus Type 11. Since rifampicin was the least soluble among the four-drugs in the FDC, its dissolution was studied.

Example 1 150.00 12:55 } Microcrystalline Cellulose | 55.00

Ascorbic Acid 300 fozs 10.00 - Pregelatinised Starch 20.00 168]

Isoniazid [7500 628 0 400.00 3347]

Microcrystalline Cellulose | 55.00 (460

Pregelatinised Starch [2000 [1es

Colloidal Silicon Dioxide [1000 ~~ - ~~ Tos

Magnesium Stearate ~~ [1000 [oss lo 0 Isr 4s lwoxr

Example 2

Ingredients [weight (mg/tab) | %wiw

AscorbicAcd 900 fo7s [Isoniazid 17500 ~~ — Je2s ~

Colloidal Silicon Dioxide [1000 ~~ [o84

Magnesium Stearate ~~ [1000 ~~ [oss | 78.2 0 i&y so less 0 5 .

Example 3

AscorbicAcid J1000 ~~ Jos4 7] : (Isoniazid [7500 628

Colloidal Silicon Dioxide [1000 —— og4

Magnesium Stearate [1000 To84 [Pregefatinised Starch [2000 [ies lo 82 20 90.7 30 98.2 Co as fees 00

Example 4 “AscobicAcid [1000 Joss

Isomiazid [7500 Tess :

Colloidal Silicon Dioxide [1000 los4 :

oo sa 0 88.2 : 98.6

Example S

Povidone (polyvinyl pyrrolidone K30) [1000 ~~ [084

Isoniazid 17500 [628 4.94 0.42

Colloidal Silicon Dioxide ~~ [1000 ~~ Jo84

Magnesium Stearate 1000 [084

Rifampicin Released (% 10 ]726 _ 83.6 90.1 — 95.2 B)4-Step Granulation Process

Rifampicin, microcrystalline cellulose or lactose, crospovidone and pregelatinised starch or. povidone were mixed. Ascorbic Acid was dissolved in water and then pregelatinized starch dispersed in water or povidone (polyvinyl pyrolidone K30) was dissolved in water to make binder solution. The blend was granulated with the binder solution.

Isoniazid, microcrystalline cellulose or lactose were mixed the blend was granulated with pregelatinized starch dispersed in water or povidone (polyvinyl pyrolidone K30) dissolved in water.

Pyrazinamide, optionally by mixing with lactose was granulated with pregelatinized starch dispersed in water or povidone (polyvinyl pyrolidone K30) dissolved in water, separately.

Ethambutol Hydrochloride and microcrystalline cellulose or dicalcium phosphate were mixed and granulated with gelatin solution. After drying, the granules of all 4-steps were blended together and mixed with silicon dioxide, microcrystalline cellulose, crospovidone or sodium starch glycollate and magnesium stearate. The granules were compressed into tablets and coated with Opadry AMB Brown.

Example 6 [Ingredients ~~ [weight (mg/tab) ~~ |%ww ~~] 150.00 12.55

Microcrystalline Cellulose | 40.00

Ascorbic Acid 90 fors

Pregelatinised Starch 40.00 400.00 33.47

Pregelatinised Starch 49.00 [Isoniazid [75.00 : Microcrystalline Cellulose | 20.00

Pregelatinised Starch 20.00

Ethambutol HCl 275.00 23.00

Microcrystalline Cellulose | 32.00

Colloidal Silicon Dioxide [1000 Tosa

Microcrystalline Cellulose | 20.00 168]

Magnesium Stearate [1000 fos : jo ~~ fe 0] 98.1 100.7 —

Example 7 Crospovidone [1000 ~~ Jos4 Pregelatinised Starch [2000 Jie8

Pregelatinised Starch [5500 [460

Isoniazid [7500 Je

EE eo

Pregelatinised Starch 1000 ~~ [084

Colloidal Silicon Dioxide [1000 ~~ jo84

Magnesium Stearate [1000 ~~ fos

Rifampicin Released (% } j }

BT +X I 54 TT 98.7

Example 8

Ingredients. [weight mg/tab [% wiw 1 12.55 ! 4.60 0.25 0.84

[Isoniazid J7500 ~~ e288

Microcrystalline Cellulose [1000 ~~ Jo84

Pregelatinised Starch [1000 ~~ [084

Colloidal Silicon Dioxide [1000 ~~ Tos4 =

Magnesium Stearate {1000 ~~ fo84 0 fess

Example 9

Povidone (polyvinyl pyrrolidone K30) [1000 Tosa

Isoniazid ~~ [7500 Te28

Dicalcium phosphate [5500 [460

Colloidal Silicon Dioxide [1000 Joss

Magnesium Stearate ~~ [1000 loss

20 ‘8s3 3 {ex 0] «1% 0]

Example 10

Rifampicin______ | 150.00 12.55 [Lactose [55.00

Ascorbic Acid 15.00

Povidone (polyvinyl pyrrolidone K30) [1000 [084

Pyrazinamide 1400.00

Povidone (polyvinyl pyrrolidone K30) 10.00 [084 (Isoniazid |75.00

Lactose 147.00

Povidone (polyvinyl pyrrolidone K30

Ethambutol HCI ~~ [275.00 23.00

Dicalcium phosphate 65.00

Gelatin [seo Joa

Colloidal Silicon Dioxide ooo foes 60.00

Magnesium Stearae [1000 Jos

Time (Min Rifampicin Released (% 10 71.8 20 83.6 30 91.5 45 958 _

Disintegration test as per indian Pharmacopoeia:

One tablet was introduced in each tube of disintegration test basket and covered with a disc in each tube. The assembly was suspended in purified water at (37+2° C) and operated till all six tablets disintegrated completely. The following table gives the disintegration time observed for tablets prepared as in respective examples.

Disintegration time in minutes or 67 0000000000] 2 [80 0000000000000 4 6-7 6 45 5

E

EE

5

Claims

Claim +5 I. An improved process for the preparation of an antitubercular pharmaceutical composition in fixed dose combination containing four drugs rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride compnsing : . : a) mixing rifampicin with excipients free of any surfactant followed by wet granulation of

10. resulting mixture with a binder material to obtain granules of said mixture and thereafter ; subjecting the said granules to drying; - - } b) mixing isoniazid with excipients free of any surfactant followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter 1s subjecting the said granules to drying; - c) mixing pyrazinamide with excipients free of any surfactant followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying; : d) mixing ethambutol hydrochloride with excipients free of any surfactant_followed by wet granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafier subjecting the said granules to drying; mo IS: SL

£).. mixing the granules obtained in steps a), b), ¢) and d) with excipients free of any surfactant .to obtain a lubricated blend; f) converting the resulting lubricated blend into a solid dosage form + - ce
2. An improved process for the preparation of an antitubercular pharmaceutical composition in ~~ fixed dose combination containing four drugs rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride comprising :

is tinted: 05-02-21 z 03: 122 (PCT) CLMSPAMD Sn 01254310 -INO100093 a) mixing rifampicin with excipients free of any surfactant followed by wet granulation of _ resulting mixture with a binder material to obtain granules of -said mixture and thereafter © - - subjecting the said granules to drying; A - b) mixing isoniazid and pyrazinamide with excipients free of any surfactant followed by wet 40 granulation of resulting mixture with a binder material to obtain granules of said mixture and thereafter subjecting the said granules to drying. c) mixing ethambutol hydrochloride with excipients free of any surfactan/ followed by wet Ce granulation of resulting mixture with a binder material to obtain granules of said mixture 4s and thereafter subjecting the said granules to drying; . : d) mixing the granules obtained in steps a), b) and €) with excipients free of any surfactant to obtain a lubricated blend, : s0 ¢) converting the resulting lubricated blend into a solid dosage form.”
3. A process as claimed in claim 1 or 2 wherein the solid dosage form is a film coated tablet. ss
4. A process as claimed in claim 1 or 2 wherein the solid dosage form is a capsule. . .
5. Aprocess as claimed in claim 1 or 2 wherein the solid dosage form is formulated as granules for preparing a suspension. 60 ’ . ~~
6. A process as claimed in claim 1 or 2 wherein excipients are selected from one or more of + : antioxidants, inert diluents, disintegrants, lubricating agents and coating agents. 65

7. A process as claimed in claim 1 or 2 wherein said binder material is selected from onc or more of gelatin, starch, povidone, hydroxypropylmethyi cellulose, hydroxypropyl cellulose, pregelatinized starch, sucrose, acacia, alginic acid, sodium alginate. 70 "mn rn — FIRE

8. A process as claimed in claim 6 wherein said inert diluent is selected trom one or more of calcium carbonate, calcium sulfate, dextrates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, lactose, mannitol, microcrystalline ceilulose, starch, polymethacrylates.

9. A process as claimed in claim 6 wherein said antioxidant is selected from one or more of sodium metabisulphite, sodium sulphite, a-tocopherol, ascorbic acid, sodium ascorbate, malic acid, propylgallate.

10. A process as claimed in claim 6 wherein said coating agent is selected from one or more of hydroxypropyl! methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic acid copolymers, cellulose acetate phthalate, cetyl alcohol, shellac, microcrystalline wax.

11. A process as claimed in claim 1 or 2 wherein binder matenal used is pregelatinised starch, povidone, gelatin or mixture thercot.

12. A process as claimed in claim1, 2 or 11 wherein binder material is used in the range of 110 20 wt % of the total composition.

13. A process as claimed in claim | wherein said binder material used in step a), b) and/or ¢) is pregealtinised starch or povidone and said binder material used in step d) is gelatin.

14. A process as claimed in claim 2 wherein said binder material used in step a) and/or b) is pregealtinised starch or povidone and said binder material used in step c) is gelatin.

15. A process as claimed in claim 1, 2, 13 or 14 wherein pregelatinised starch is used as a binder material in the range of 1 to IS wt % of the 10tal composition.

16. A process as claimed in claim 1, 2, 13 or 14 wherein pregelatinised starch is used as a binder material in the range of 3 to 12 w1 % of the total composition.

17. A process as claimed in claim 1, 2, 13 or 14 wherein gelatin is used as a binder material in the range of 0.2 to 2 wt % of the total composition.

18. A process as claimed in claim 1, 2, 13 or 14 wherein povidone is used as a binder material in the range of 0.2 to 5 wt % of the total composition.

19. A process as claimed in claim 6 wherein the antioxidant used is ascorbic acid, sodium ascorbate or mixture thereof.

20. A process as claimed in claim 19 wherein antioxidant is used in the range of 0.1 to 1.5 wt % of the total composition.

21. A process as claimed in claim 19 wherein antioxidant is used in the range of 0.1 10 1 I5 wt % of the total composition.

22. A process as claimed in claim 6 wherein the disintegrant is crospovidone. sodium : starch glycolate or mixture thereof

23. A process as claimed in claim 22 wherein disintegrant is used in the range of 1 to 10 wt % of the total composition.

24. A process as claimed in claim 22 wherein disintegrant is used in the range of 2 10 8 wi % of the total composition.

25. A process as claimed in claim 1 or 2 wherein drying of said granules is carried out between temperature range of 40° C to 80° C.

26. A process as claimed in claim | or 2 wherein drying of said granules is carried out between temperature range of 50° C to 70° C.

27. A composition prepared according to claim 1 or.2 wherein amount of rifampicin 1s between 60 to 600 mg.

28. A composition prepared according to claim 1 or 2 wherein amount of ethambutol S hydrochloride is between 100 to 1000 mg.

29. A composition prepared according to claim | or 2 wherein amount of isoniazid is between 30 to 300 mg.

30. A composition prepared according to claim | or 2 wherein amount of pyrazinamide is between 150 to 1200 mg.

31. A stable, bioavailable composition prepared according to claim | or 2 wherein amount of said rifampicin is between 60 to 600 mg, amount of said ethambutol hydrochloride is between 100 to 1000 mg, amount of said isoniazid is between 30 to 300 mg and amount of said pyrazinamide is between 150 to 1200 mg.

32. A process for manufacturing a pharmaceutical composition in a solid dosage form as claimed in any one of claims 1 to 26 wherein said rifampicin is used in an amount ranging from 60 to 600 mg, said ethambutol hydrochloride is used in an amount ranging from 100 to 1000 mg, said isoniazid is used in an amount ranging from 30 to 300 mg and said pyrazinamide is used in an amount ranging from 150 to 1200 mg.

33. A process as claimed in claim 32 wherein the solid dosage form is a tablet.