KR20160034983A - Anti-tuberculosis stable pharmaceutical composition in a form of a dispersible tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation - Google Patents

Abstract

The present invention relates to a fixed dose oral pharmaceutical composition for use in the treatment of tuberculosis, and a method of preparing the same, wherein the oral pharmaceutical composition comprises a) granules comprising isoniazid and one or more granular excipients, b) A granulate comprising lipapentin and one or more intragranular excipients, and c) one or more extragranular excipients.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a stable anti-tuberculous pharmaceutical composition in the form of a dispersion containing an isoniazid granule and a lipopentin granule, and a method for producing the same. [0002]

The present invention relates to a chemically stable anti-tuberculous fixed dose pharmaceutical composition in the form of a dispersion containing two active ingredients, namely, lipapentin and isoniazid, as separate granules. The present invention also provides a method of producing such an anti-tuberculous pharmaceutical composition.

Tuberculosis (TB), an infectious disease, is the leading cause of death worldwide by a single human pathogen, and is associated with diseases such as acquired immunodeficiency syndrome (AIDS), malaria, diarrhea, leprosy and all other combined tropical diseases (Zumla A, Grange J. BMJ (1998) 316, 1962-1964). Currently, about one third of the world's population is infected with Mycobacterium tuberculosis ( Mtb ), an agent that causes the disease, and 10% of those infected have clinical disease do. According to the WHO figures, the rate of TB outbreaks in humans has declined, but the number of cases continues to increase steadily. The most affected areas are in developing countries, where poverty, other diseases, and inadequate health care are factors. By killing about 1.6 million people each year, TB is the second leading cause of death worldwide after HIV / AIDS.

Currently, for the effective treatment of TB, a combination of at least the following drugs, isoniazid, rifampin and pyrazinamide is given to the patient in an initial treatment period of 8 weeks, during which time these drugs are used in combination to kill the rapidly proliferating Mtb population, In addition, the occurrence of drug resistance is prevented. This initial treatment regimen is followed by a sustained period of 24 weeks during which the combination of at least the following drugs, isoniazid and rifapentin is given to the patient. Such prolonged combination therapy is not always successful, especially in patients with drug-resistant strains. Also, adherence in a relatively long course of treatment is generally poor. Such non-compliance can lead to treatment failure and develop drug resistance.

For the control of the emergence of drug-resistant tuberculosis, WHO used the fixed dose combination (FDC) in the form of tablets containing two different active ingredients in the same formulation, namely isoniazid and rifapentin in a fixed ratio . FDC in tablet form has been previously disclosed.

International patent application WO 2007/43542 in the name of SUKA PHARMACEUTICAL CO., LTD. Discloses pharmaceutical compositions and kits for the treatment of tuberculosis. This pharmaceutical composition comprises an oxazole compound, lipapentin and isoniazid, which may be in the form of tablets.

Chinese Patent No. 1717912 in the name of GUANXIN CEN discloses pharmaceutical compositions comprising rifapentin and isoniazid, which may be in the form of tablets.

Chinese patent no. 185728 in the name of SHUAIHUA MEDICINE SCI TECH CO discloses a sustained release formulation (implant) comprising rifapentin and isoniazid, which is in the form of tablets .

However, it is well known to those skilled in the art that the use of such FDCs can reduce the bioavailability of rifapentin due to undesired chemical reactions, especially with isoniazid under catalytic conditions of an acidic stomach environment (Prasad B. et al. et al., J. Pharm. Biomed. Anal. 2006; 41: 1438-1441.).

Thus, there remains a need for a stable anti-tuberculous oral pharmaceutical composition comprising both lipapentin and isoniazid which is capable of reducing the bioavailability of rifapentin and preventing undesired chemical reactions with isoniazid.

Applicants have discovered that it is possible to provide such oral pharmaceutical compositions having the satisfactory bioavailability of both active ingredients by separately granulating the two active ingredients and introducing them into the pharmaceutical composition.

Object of the Invention

A first object of the present invention is a fixed dose oral pharmaceutical composition in the form of a dispersion for use in the treatment of tuberculosis, said oral pharmaceutical composition comprising:

a) Granules comprising isoniazid and one or more granular excipients,

b) A granulate comprising lipapentin and at least one granular excipient, and

c) One or more extragranular excipients.

A still further object of the present invention is a method for the manufacture of a pharmaceutical composition for oral use according to the present invention, which comprises a separate isoniazid granulation step and a lipopentin granulation step.

invent:

The pharmaceutical compositions according to the invention are chemically stable and suitable for the treatment of tuberculosis by oral administration.

By "chemically stable" is meant the total amount of impurities formed from riapapentin after storage for less than 6 months at 60% RH to 75% RH at a constant temperature holding temperature, including the typical and customary working environment of 25 & (W / w) based on the weight of lipapentin initially present in the tablet and the total amount of impurities formed from the isoniazid is less than 2% (w / w) based on the weight of isoniazid initially present in the tablet it means.

Without wishing to be bound by any theory, it is believed that the tablets according to the present invention are particularly suitable for the preparation of the active ingredient of both of the above, since the reaction between the lipapentin and isoniazid under the above conditions is restricted due to the particular configuration of the oral pharmaceutical composition Are considered to allow good bioavailability.

The present oral pharmaceutical composition is a fixed dose composition. By "fixed dose composition" is meant a single unit of administration, i.e., a combination of the two drugs or active ingredients presented in tablets.

The oral pharmaceutical composition comprises two active ingredients, namely, lipapentin and isoniazid, and a pharmaceutically acceptable excipient.

More precisely, the present oral pharmaceutical composition comprises granules (lipapentin granules) comprising granules (isoniazid granules) comprising isoniazid and one or more granular excipients, lipapentin and one or more granular excipients, and one or more Extragranular excipients.

The granules of the present oral pharmaceutical composition exhibit a size of less than 0.710 mm as required by the US Pharmacopoeia for the dissolution profile.

The oral pharmaceutical composition is in the form of a dispersible tablet, for example, to promote its uptake by the child. Such a dispersion tablet is disintegrated in a liquid, e.g., water, prior to administration.

The dispersion tablet may be a single layer dispersion or a double layer dispersion tablet.

According to an embodiment wherein the oral pharmaceutical composition is a bi-layer dispersible tablet, one layer of the oral pharmaceutical composition comprises isoniazid granules and at least one portion of an extragranular excipient. Another layer of the oral pharmaceutical composition comprises a lipapentin granulate and at least a residual extragranular excipient.

Extragranular excipients include stabilizers. The stabilizer is selected from the group comprising sodium ascorbate, sodium metabisulfite, disodium EDTA, butylhydroxylated toluene, citric acid, tocopherol, butylhydroxyanisole, ascorbic acid, tartaric acid, and mixtures thereof. Preferably, the extragranular excipient is selected from sodium ascorbate, sodium metabisulfite, and mixtures thereof.

The extragranular excipient may also include a compound selected from the group including diluents, disintegrants, lubricants, solubilizers, flavoring agents, sweeteners, glidants, and mixtures thereof.

Diluents include microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, mannitol, and mixtures thereof, preferably microcrystalline cellulose.

Disintegrants include crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose, sodium starch glycolate, corn starch, low substituted hydroxypropyl cellulose, alginic acid, preferably crospovidone, sodium starch glycolate, . ≪ / RTI >

The lubricant may be a finely divided lubricant, for example magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, zinc stearate, glyceryl behenate and mixtures thereof, preferably calcium stearate, magnesium stearate And mixtures thereof.

Solubilizing agents include sodium lauryl sulfate, Tween 80, PEG 4000 and mixtures thereof, preferably sodium lauryl sulfate.

The flavoring agents include mint hometown, orange flavor, cherry flavor, strawberry flavor and mixed fruit flavor.

The sweetening agents include aspartame, sucrose, xylitol and potassium acesulfame, preferably aspartame.

Glydant includes colloidal silicon dioxide, magnesium oxide, magnesium silicate, preferably colloidal silicon dioxide.

According to certain embodiments, the intragranular excipients present in the isoniazid granules are different from those present in the lipapentin granules.

Granule excipients are selected from the group comprising diluents, disintegrants, granulating binders, stabilizers, and mixtures thereof.

Diluents, disintegrants and stabilizers are as mentioned above. These may be the same as the diluents, disintegrants and stabilizers used as extragranular excipients, or they may be different.

The granulating binder is selected from povidone such as povidone K30 or povidone K90, hydroxypropylcellulose, polyvinyl alcohol, corn starch, pregelatinized starch and mixtures thereof, preferably povidone, or hydroxypropylcellulose or pregelatinized starch Can be selected.

The oral pharmaceutical composition according to the present invention can be packed in any suitable packaging, for example, in a double aluminum blister package, thanks to a wrapper.

According to some embodiments, the oral pharmaceutical composition comprises 100 mg to 400 mg of riapapentin and 40 mg to 400 mg of isoniazid.

Treatment of tuberculosis is a long-term treatment. For example, a typical prescription dose is 600 mg twice a week for two months, with an interval of three consecutive days (72 hours) between doses, which is combined with other anti-TB drugs for up to 2 months in the initial TB treatment . The above 2-month period, 600 mg once a week, follows a 4-month follow-up by direct observation with isoniazid or another appropriate anti-tuberculosis drug. The usual dosage regimen for isoniazid is from 5 mg / kg to 300 mg (daily) in single doses and from 15 mg / kg to 900 mg / day (2 to 3 times / week).

Due to this type of treatment, it is very useful to be able to use other tablets differing in the ratio of riapapentin / azoniazide.

According to some embodiments, the ratio of riapapentin: isoniazid is comprised from 3: 1 to 1: 0.5, and preferably the ratio of riapapentin: isoniazid is 1: 1.

More specifically, the tablets according to the present invention may contain 150 mg of lipapentin and 150 mg of isoniazid, 120 mg of lipapentin and 50 mg of isoniazid, 90 mg of riapapentin and 50 mg of isoniazid.

According to a preferred embodiment, wherein the stabilizer is sodium ascorbate, the ratio of sodium ascorbate to ripapentin comprises 1: 100 to 1: 0.1, preferably 1:40 to 1:20, more preferably 1:35 To 1:25, and even more preferably 1:30.

Percentages are expressed as weight relative to the total weight of the tablet.

According to certain embodiments, the oral pharmaceutical composition comprises:

- 5% to 50%, preferably 10% to 30%, even more preferably 14% to 22% of riapapentin, and

- 5% to 50%, preferably 7.5% to 30%, even more preferably 9% to 17% of isoniazid.

According to some embodiments, the oral pharmaceutical composition comprises from 0.1% to 80%, preferably from 20% to 70%, more preferably from 40% to 60% of a diluent.

According to some embodiments, the oral pharmaceutical composition comprises from 0.1% to 50%, preferably from 1% to 40%, more preferably from 1.5% to 25% of a disintegrant.

According to certain embodiments, the oral pharmaceutical composition comprises from 0.1% to 10%, preferably from 1% to 7.5%, more preferably from 1.25% to 5% of a binder.

According to some embodiments, the oral pharmaceutical composition comprises 0.1% to 1%, preferably 0.2% to 0.8%, more preferably 0.4% to 0.6% of a lubricant.

According to some embodiments, the oral pharmaceutical composition comprises less than 2%, preferably less than 1.5%, more preferably less than 1% solubilizing agent.

According to certain embodiments, the oral pharmaceutical composition comprises from 0.1% to 2%, preferably from 0.2% to 1.5%, more preferably from 0.5% to 0.9% of a stabilizer.

According to some embodiments, the oral pharmaceutical composition comprises less than 2%, preferably less than 1.5%, more preferably less than 1.1% of glidant.

According to some embodiments, the oral pharmaceutical composition comprises 0.1% to 5%, preferably 0.5% to 3%, more preferably 0.9% to 2% of a flavoring agent.

According to some embodiments, the oral pharmaceutical composition comprises from 0.1% to 5%, preferably from 0.25% to 4%, more preferably from 0.4% to 3% of a sweetening agent.

According to some embodiments, the oral pharmaceutical composition in the form of a dispersion is characterized by a hardness of 50 N to 200 N, preferably 75 N to 175 N, more preferably 100 N to 160 N.

The hardness is measured in a hardness tester. The tablet is placed between two arms, one arm being a static arm and the other arm pushing the tablet against the static arm to break the tablet. The pressure applied for the disruption of the tablet is recorded by the device. Values are recorded in Newton or KiloPascal units.

According to certain embodiments, the oral pharmaceutical composition in the form of a finely divided tablet is characterized by less than 5%, preferably less than 2.5%, more preferably less than 1%.

The degree of wear is measured on standard equipment known as a friabilator. Twenty tablets are weighed and loaded into the device (or 6 g of tablets are loaded into the device). The device is then rotated for a number of revolutions of 100 at 25 RPM / min. Remove the tablets and weigh them. The percent loss is determined by the formula: [(weight of pre-spin tablet - weight of tablet after spin) / initial weight] X 100.

According to some embodiments, the pharmaceutical composition for oral use in the form of a dispersion is characterized in that the dispersion-defined disintegration time in water at 25 占 폚 is less than 5 minutes, preferably less than 3 minutes, more preferably less than 2 minutes.

The disintegration time is measured in 900 mL of purified water. The temperature is maintained at 25 占 폚. The disintegration time device consists of 6 tubes with a 2 mm sieve at the base of each tube, and the tube is operated at 30 times of immersion / min. One tablet is placed in each tube and the device is operated until the complete mass of the tablet has disintegrated / disintegrated, i. E., Passed through a 2 mm sieve.

According to yet another object, the present invention relates to a method for preparing an oral pharmaceutical composition comprising a separate isoniazid granulation step and a lipopentin granulation step.

According to certain embodiments, a method of making a monolayer tablet comprises the steps of:

a) Preparing an isoniazid granule,

b) Preparing lipapentin granules,

c) Mixing the granulate obtained from step a) and step b) with an extragranular excipient, and

d) Compressing the mixture of step c) to obtain tablets.

The separate granulation steps are carried out by wet granulation.

The wet granulation is carried out using an aqueous solvent, a liquid binder, an organic solvent such as isopropyl alcohol, acetone and chloroform, preferably an aqueous-based granulating composition. The granulating composition may also comprise a binder, diluent, disintegrant or a mixture thereof.

After wet granulation, the granules are dried. The granules can be sieved to improve and improve dryness.

The granules are then sieved to obtain a homogeneous granule size and granules having a size of less than 1.5 mm, preferably less than 1 mm, more preferably less than 0.710 mm can be selected and mixed homogeneously.

All extragranular excipients are mixed together except for the lubricant which is incorporated at the end of the mixing.

Prior to compression, the mixture can be sieved to have homogeneous sized particles, and thus to promote compression.

According to certain embodiments, a method of making a bi-layer tablet comprises the steps of:

a) Preparing a layer comprising an isoniazid granule and at least a portion of an extragranular excipient,

b) Preparing a layer comprising the lipapentin granules and the remainder of the extragranular excipient,

e) Compressing the layer of step a) and the layer of step b) to obtain a bilayer tablet.

The specificity of the different steps described above for single layer tablets also applies to bilayer tablets.

The step of making the layer comprises preparing granules of the active ingredient, then mixing the granules with an extragranular excipient, followed by sieving. The present invention is described in further detail in the following examples which are provided for illustrative purposes only.

Example

Example 1: Bilayer dispersion definition composition

* It is removed during drying, but not in the final product, except as a trace.

Manufacturing method of double layer dispersion definition

Microcrystalline cellulose, pregelatinized starch and sodium starch glycolate are separately sieved through 0.425 mm, 0.250 mm and 0.180 mm sieves, respectively. This material is then sieved through a 0.500 mm sieve simultaneously withripapentin.

These sieved materials are then dry blended in a fast mixer granulator for 20 minutes at 100 rpm.

They are then first granulated in a fast mixer granulator using purified water at 125 rpm and using a chopper at 1000 rpm for 3 minutes and 30 seconds. The blend is further kneaded at 150 rpm and 1000 rpm for 6 minutes in a chopper to obtain the desired core granules.

The wet granules obtained are then dried in a fluid bed dryer for 4.75 hours at an inlet temperature of 60 ° C to 70 ° C. Next, the resulting dried granules are sieved through a 0.600 mm sieve and chilled dried granules are sieved to a size of less than 0.710 mm.

Sodium ascorbate and sodium starch glycolate are sieved through a 0.180 mm sieve, and microcrystalline cellulose and sodium lauryl sulfate are sieved through a 0.425 mm sieve. These sieved materials are then blended with the selected sieved dried granules for 25 minutes at a speed of 18 rpm in a double cone blender.

Finally, the blend is lubricated with calcium stearate (sieved through a 0.250 mm sieve) for 5 minutes at a speed of 18 rpm in a double cone blender.

First, microcrystalline cellulose and sodium starch glycolate are sieved through a 0.425 mm sieve and a 0.180 mm sieve, respectively. These materials are then sieved simultaneously with the isoniazid through a 0.425 mm sieve and then dry mixed in a rapid mixer granulator for 15 minutes. The resulting blend is first granulated using a solution of povidone K30, which is initially dissolved in purified water in a rapid mixer granulator for two minutes at 100 rpm. The blend is further kneaded at 125 rpm and at 1000 rpm for 1.5 minutes at the chopper to obtain the desired core granules.

The wet granules obtained are then dried in a fluidized bed dryer at an inlet temperature of 45 ° C to 50 ° C for 15 minutes. Next, the resulting dried granules are sieved through a 0.600 mm sieve to select dried granules of less than 0.710 mm in size.

Sodium starch glycolate and mesh hull are sieved through 0.180 mm, and microcrystalline cellulose and aspartame are sieved through a 0.425 mm sieve. These sieved materials are then blended with the previously selected dry granules for 15 minutes at a speed of 18 rpm in a double cone blender.

Finally, the blend is lubricated with calcium stearate (sieved through a 0.250 mm sieve) for 5 minutes at a speed of 18 rpm in a double cone blender.

A double layer tablet was obtained by successively introducing a first blend into a first layer hopper and then a second blend into a second layer hopper, which was then coated with a 15.5 mm flat face beveled edged tooling To obtain a double layered tablet having a thickness of 5.0 mm. Its hardness is 150 N, and its disintegration time is 30 seconds.

Finally, the bilayer partition is packed in an alu-alu blister.

Study of packed dual layer dispersion definition stability data

Packed and coated bilayer tablets were studied for stability under accelerated conditions [40 ° C / 75% RH] and in real-time conditions [25 ° C / 60% RH and 30 ° C / 75% RH]. Analysis by HPLC method was performed immediately (initial), at 3 and at 6 months. The analysis by HPLC method leads to the total amount of impurities in both the lipapentin-related substance and the isoniazid-related substance.

Table 1 presents the results of decomposition of riapapentin and isoniazid under these conditions. The results indicated that the total amount of impurities in both the lipapentin-related material and the isoniazid-related material was below the specification.

Example 2: Single layer dispersion definition composition

* It is removed during drying, but not in the final product, except as a trace.

Manufacturing method of single layer dispersion definition

The granules are prepared as described in Example 1 except that the ingredients mentioned in the table above are used.

First, the lipapentin and isoniazid starter dried granules are blended with the following extragranular excipients: microcrystalline cellulose, crospovidone, sodium ascorbate, sodium starch glycolate, aspartame and mend hometown. The resulting blend is then enriched using colloidal silicon dioxide and magnesium stearate. Finally, the lubricated blend is compressed into tablets.

The resulting single layer dispersion definition dimensions are 20 mm x 10 mm x 6.34 mm, respectively. His hardness is 155 N and his disintegration time is 100 seconds.

The packed monolayer distribution was studied for stability as in Example 1. Table 2 shows the decomposition of ripapentin and isoniazid under these conditions. The results showed that the total impurities in both the lipapentin-related material and the isoniazid-related material were below the specification.

Claims (8)

a) granules comprising isoniazid and one or more granular excipients,
b) granules comprising lipapentin and one or more granular excipients, and
c) one or more extragranular excipients
Of fixed-dose oral pharmaceutical form for use in the treatment of tuberculosis. The pharmaceutical composition according to claim 1, which is chemically stable. 3. The method according to claim 1 or 2,
A layer comprising isoniazid granules (a) and at least one extragranular excipient, and
- a layer comprising lipapentin granules (b) and at least one extragranular excipient
Or a pharmaceutically acceptable salt thereof. 4. The oral pharmaceutical composition according to any one of claims 1 to 3, wherein the ratio of lipapentin: isoniazid is comprised from 3: 1 to 1: 0.5, and preferably the ratio is 1: 1. A method for preparing an oral pharmaceutical composition according to any one of claims 1 to 4, characterized in that it comprises a separate isoniazid granulation step and a lipopentin granulation step. 6. Process according to claim 5, characterized in that the preparation of granules is preferably carried out by wet granulation in an aqueous solvent. The method according to claim 5 or 6,
a) preparing an isoniazid granule,
b) preparing lipapentin granules,
c) mixing the granulate obtained from step a) and step b) with an external granule, and
d) compressing the mixture of step c) to obtain tablets
≪ / RTI > 8. The method according to any one of claims 5 to 7,
a) preparing an isoniazid granule,
b) mixing the granulate obtained from step a) with at least a part of an extragranular excipient,
c) preparing the lipapentin granules,
d) mixing the granules obtained from step c) with the remaining part of the extragranular excipient, and
e) compressing the mixture of step b) and step d) to obtain a bilayer tablet
≪ / RTI >