CA2617000C - Methods for preparing nevirapine hemihydrate and an aqueous suspension thereof - Google Patents
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- CA2617000C CA2617000C CA2617000A CA2617000A CA2617000C CA 2617000 C CA2617000 C CA 2617000C CA 2617000 A CA2617000 A CA 2617000A CA 2617000 A CA2617000 A CA 2617000A CA 2617000 C CA2617000 C CA 2617000C
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Abstract
The invention relates to a method for preparing nevirapine hemihydrate and a method for preparing an aqueous suspension of nevirapine hemihydrate. The method for preparing nevirapine hemihydrate which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt; (b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.
Description
METHODS FOR PREPARING NEVIRAPINE HEMIHYDRATE AND AN AQUEOUS
SUSPENSION THEREOF
This is a divisional application of Canadian Patent Application No. 2,301,646 filed August 11, 1998.
Background of the Invention (1) Field of the Invention The invention relates to a novel composition of matter which is a pharmaceutical suspension comprising nevirapine hemihydrate.
The subject matter of this divisional application is directed to a method of preparing nevirapine hemihydrate and a method of preparing an aqueous suspension of nevirapine hemihydrate.
The subject matter of the parent application has been restricted to pharmaceutical compositions comprising nevirapine hemihydrate. However, it should be understood that the expression "the invention" and the like, as used herein, encompasses the subject matter of both the parent application and this divisional application.
SUSPENSION THEREOF
This is a divisional application of Canadian Patent Application No. 2,301,646 filed August 11, 1998.
Background of the Invention (1) Field of the Invention The invention relates to a novel composition of matter which is a pharmaceutical suspension comprising nevirapine hemihydrate.
The subject matter of this divisional application is directed to a method of preparing nevirapine hemihydrate and a method of preparing an aqueous suspension of nevirapine hemihydrate.
The subject matter of the parent application has been restricted to pharmaceutical compositions comprising nevirapine hemihydrate. However, it should be understood that the expression "the invention" and the like, as used herein, encompasses the subject matter of both the parent application and this divisional application.
(2) Description of the Related Arts Nevirapine, or 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, is a known agent for the treatment of infection by HIV-1 (human immunodeficiency virus, type 1), which acts through specific inhibition of HIV-1 reverse transcriptase. Its synthesis and use are described in various publications including, inter alia, U.S. Patent Nos. 5,366,972; 5,571,912; and 5,569,760 and Published European Patent Application No. 0 429 987. Viramune tablets, a pharmaceutical comprising nevirapine in tablet form, has recently been approved by the U.S. Food and Drug Administration for use in the treatment of HIV-1 infection.
Angel et al. [Proc. 50th Annual Meeting of the Electron Microscopy Society of America, pp. 1326-1327 (1992)] have disclosed that nevirapine exists as the hemihydrate stable form and as the anhydrous metastable form. This same reference describes an attempt to make an aqueous suspension of nevirapine, suitable for pediatric use, from the anhydrous form of the compound. The attempt was unsuccessful because, when formulated in aqueous suspension, the anhydrous nevirapine slowly converted to the hemihydrate form, yielding crystals of the hemihydrate which, over time, grew so large as to adversely affect drug dissolution and pharmaceutical performance.
la Summary of the Invention The invention is an aqueous suspension of the hemihydrate form of nevirapine. It has been found, unexpectedly, that, when placed in aqueous suspension, the crystal size of the hemihydrate remains stable over time.
For this reason, aqueous suspensions of nevirapine hemihydrate are pharmaceutically acceptable. Nevirapine hemihydrate may be used to treat HIV-1 infection or to prepare a medicament for treating HIV-1 infection.
According to one aspect of the present invention, there is provided a method for preparing an aqueous suspension of nevirapine which method comprises admixing nevirapine hemihydrate, having a particle size between about 1 and 150 microns, with water.
According to another aspect of the present invention, there is provided a pharmaceutical composition consisting essentially of nevirapine hemihydrate, having a particle size between about 1 and 150 microns, and water.
According to one aspect of the invention of the present divisional invention, there is provided a method for preparing nevirapine hemihydrate which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt; (b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.
According to another aspect of the invention of the present divisional invention, there is provided a method for preparing an aqueous suspension of nevirapine hemihydrate wherein the crystal size of the nevirapine hemihydrate is pharmaceutically acceptable and remains stable over time, which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield an acid addition salt; (b) treating the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; (d) washing the separated nevirapine hemihydrate with water; (e) optionally milling the dried nevirapine hemihydrate to obtain a particle size that is suitable for producing a pharmaceutically acceptable suspension, if the particles are not already of such size;
and, (f) mixing the dried and optionally milled nevirapine hemihydrate with water, to obtain the aqueous suspension.
Detailed Description of the Invention Anhydrous nevirapine can be made by any of several known methods, including those described in the references mentioned above.
The hemihydrate is conveniently produced by recrystallization of the anhydrous material from an aqueous medium. This can be accomplished by treating an aqueous suspension of the anhydrous material, which is a free base, with a strong acid, such as HC1, to yield the acid addition salt. The salt is, in turn, treated with a strong base, such as NaOH, to yield the free base as a precipitate, in the hemihydrate form. The precipitate is removed from the aqueous medium by filtration, washed with water and dried -2a-until the water content is between about 3.1 and 3.9% by weight. Further drying, which would convert the hemihydrate to the anhydrous form is to be avoided. The term hemihydrate is intended to refer to nevirapine which contains about 0.5 mole of water.
For use in a pharmaceutically acceptable aqueous suspension, the particle size of the hemihydrate should be between about 1 and 150 microns in diameter. The hemihydrate produced as described above can be milled, if necessary, so that particle size will fall within this range.
A pharmaceutically acceptable aqueous suspension of nevirapine hemihydrate can be made by adding the hemihydrate to purified water, in ratios from 1 to 50 mg nevirapine hemihydrate to 1 mL of water, followed by agitation. The formulation can additionally comprise conventional pharmaceutical additives, such as, but not limited to, suspending -2b-agents and/or viscosity thickening agents such as, for example cellulose-basea poiymers or synthetic polymers, preferably cross-linked polymers such as the carbomers;
wetting agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan fatty acid esters (polysorbates); sweetening or flavoring agents, such as sucrose; and preservatives, such as, for example, the parabens.
By way of non-limiting description, a typical formulation in accordance with the invention would be one as described in the following table.
Constituent Range of Amount (g/l00 mL) Nevirapine Hemihydrate 0.1 - 50 Carbomer 934P, NF 0.17 - 0.22 Polysorbate 80, NF 0.01 - 0.2 Sorbitol Solution, USP 5- 30 Sucrose, NF 5 - 30 Methylparaben, NF 0.15 - 0.2 Propylparaben, NF 0.02 - 0.24 Sodium Hydroxide, N.F.* q.s. to pH 5.5 - 6.0 Purified Water, USP q.s. ad 100.0 mL
*20% solution prepared The invention is furthei illustrated by the following non-limiting examples.
Angel et al. [Proc. 50th Annual Meeting of the Electron Microscopy Society of America, pp. 1326-1327 (1992)] have disclosed that nevirapine exists as the hemihydrate stable form and as the anhydrous metastable form. This same reference describes an attempt to make an aqueous suspension of nevirapine, suitable for pediatric use, from the anhydrous form of the compound. The attempt was unsuccessful because, when formulated in aqueous suspension, the anhydrous nevirapine slowly converted to the hemihydrate form, yielding crystals of the hemihydrate which, over time, grew so large as to adversely affect drug dissolution and pharmaceutical performance.
la Summary of the Invention The invention is an aqueous suspension of the hemihydrate form of nevirapine. It has been found, unexpectedly, that, when placed in aqueous suspension, the crystal size of the hemihydrate remains stable over time.
For this reason, aqueous suspensions of nevirapine hemihydrate are pharmaceutically acceptable. Nevirapine hemihydrate may be used to treat HIV-1 infection or to prepare a medicament for treating HIV-1 infection.
According to one aspect of the present invention, there is provided a method for preparing an aqueous suspension of nevirapine which method comprises admixing nevirapine hemihydrate, having a particle size between about 1 and 150 microns, with water.
According to another aspect of the present invention, there is provided a pharmaceutical composition consisting essentially of nevirapine hemihydrate, having a particle size between about 1 and 150 microns, and water.
According to one aspect of the invention of the present divisional invention, there is provided a method for preparing nevirapine hemihydrate which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt; (b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.
According to another aspect of the invention of the present divisional invention, there is provided a method for preparing an aqueous suspension of nevirapine hemihydrate wherein the crystal size of the nevirapine hemihydrate is pharmaceutically acceptable and remains stable over time, which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield an acid addition salt; (b) treating the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; (d) washing the separated nevirapine hemihydrate with water; (e) optionally milling the dried nevirapine hemihydrate to obtain a particle size that is suitable for producing a pharmaceutically acceptable suspension, if the particles are not already of such size;
and, (f) mixing the dried and optionally milled nevirapine hemihydrate with water, to obtain the aqueous suspension.
Detailed Description of the Invention Anhydrous nevirapine can be made by any of several known methods, including those described in the references mentioned above.
The hemihydrate is conveniently produced by recrystallization of the anhydrous material from an aqueous medium. This can be accomplished by treating an aqueous suspension of the anhydrous material, which is a free base, with a strong acid, such as HC1, to yield the acid addition salt. The salt is, in turn, treated with a strong base, such as NaOH, to yield the free base as a precipitate, in the hemihydrate form. The precipitate is removed from the aqueous medium by filtration, washed with water and dried -2a-until the water content is between about 3.1 and 3.9% by weight. Further drying, which would convert the hemihydrate to the anhydrous form is to be avoided. The term hemihydrate is intended to refer to nevirapine which contains about 0.5 mole of water.
For use in a pharmaceutically acceptable aqueous suspension, the particle size of the hemihydrate should be between about 1 and 150 microns in diameter. The hemihydrate produced as described above can be milled, if necessary, so that particle size will fall within this range.
A pharmaceutically acceptable aqueous suspension of nevirapine hemihydrate can be made by adding the hemihydrate to purified water, in ratios from 1 to 50 mg nevirapine hemihydrate to 1 mL of water, followed by agitation. The formulation can additionally comprise conventional pharmaceutical additives, such as, but not limited to, suspending -2b-agents and/or viscosity thickening agents such as, for example cellulose-basea poiymers or synthetic polymers, preferably cross-linked polymers such as the carbomers;
wetting agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan fatty acid esters (polysorbates); sweetening or flavoring agents, such as sucrose; and preservatives, such as, for example, the parabens.
By way of non-limiting description, a typical formulation in accordance with the invention would be one as described in the following table.
Constituent Range of Amount (g/l00 mL) Nevirapine Hemihydrate 0.1 - 50 Carbomer 934P, NF 0.17 - 0.22 Polysorbate 80, NF 0.01 - 0.2 Sorbitol Solution, USP 5- 30 Sucrose, NF 5 - 30 Methylparaben, NF 0.15 - 0.2 Propylparaben, NF 0.02 - 0.24 Sodium Hydroxide, N.F.* q.s. to pH 5.5 - 6.0 Purified Water, USP q.s. ad 100.0 mL
*20% solution prepared The invention is furthei illustrated by the following non-limiting examples.
Example I.
Prenaration of nevirapine hemihvdrate A glass lined reactor containing 318 Kg of nevirapine (anhydrous) is charged with 319 Kg of 37% HCl at a flow rate to maintain the internal temperature below 35 C.
The mixture is agitated at 25-35 C until all_material is dissolved. The solution is filtered and diluted with 1601iters of purified water. The solution is neutralized with a 25% sodium hydroxide solution, while maintaining the temperature below 40 C. The resulting crystalline suspension is cooled to 15-20 C for 30 minutes. The crystals are centrifuged io and washed with purified water and dried at 30-40 C. The crystals are then dried under vacuum using a conventional vacuum tumble dryer for 8-24 hours, an air circulation tray dryer for 24-72 hours, or a Titus centrifuge dryer (TZD) for 1 to 8 hours. The' drug substance, which is the hemihydrate, is dried until the water content is between 3.1 - 3.9% as determined by a moisture balance on 100 C for 30 min.
Example 2 Prenaration of neviranine hemihvdrate 26 g of nevirapine (anhydrous) are suspended in 100 mL of water. To the stirred mixture is added 30 mL of concentrated hydrochloric acid with cooling to maintain the temperature below 30 C. After 10-to 20 minutes, the colored solution is filtered and neutralized by the addition of 14.4 g sodium hydroxide in 50 mL of water. The resulting precipitate is filtered and washed with water. The wet crystalline material is transferred to trays and dried at 35-45 C until a water content of 3.1 to 3.9%
is obtained.
The melting point of the resulting hemihydrate is 242-245 C and analyzes for 3.1 to 3.6% of water, or about 0.5 mole of water.
Prenaration of nevirapine hemihvdrate A glass lined reactor containing 318 Kg of nevirapine (anhydrous) is charged with 319 Kg of 37% HCl at a flow rate to maintain the internal temperature below 35 C.
The mixture is agitated at 25-35 C until all_material is dissolved. The solution is filtered and diluted with 1601iters of purified water. The solution is neutralized with a 25% sodium hydroxide solution, while maintaining the temperature below 40 C. The resulting crystalline suspension is cooled to 15-20 C for 30 minutes. The crystals are centrifuged io and washed with purified water and dried at 30-40 C. The crystals are then dried under vacuum using a conventional vacuum tumble dryer for 8-24 hours, an air circulation tray dryer for 24-72 hours, or a Titus centrifuge dryer (TZD) for 1 to 8 hours. The' drug substance, which is the hemihydrate, is dried until the water content is between 3.1 - 3.9% as determined by a moisture balance on 100 C for 30 min.
Example 2 Prenaration of neviranine hemihvdrate 26 g of nevirapine (anhydrous) are suspended in 100 mL of water. To the stirred mixture is added 30 mL of concentrated hydrochloric acid with cooling to maintain the temperature below 30 C. After 10-to 20 minutes, the colored solution is filtered and neutralized by the addition of 14.4 g sodium hydroxide in 50 mL of water. The resulting precipitate is filtered and washed with water. The wet crystalline material is transferred to trays and dried at 35-45 C until a water content of 3.1 to 3.9%
is obtained.
The melting point of the resulting hemihydrate is 242-245 C and analyzes for 3.1 to 3.6% of water, or about 0.5 mole of water.
Examtfle 3 Preparation of aaueous 50 me/5 ml Dharmaceutical suspension of neviranine hemihvdrate Comnosition Constituent Amount (g/100 mL) Nevirapine Hemihydrate 1.035 Carbomer 934P, NF 0.2100 Polysorbate 80, NF 0.05000 Sorbitol Solution, USP 23.13 Sucrose, NF 15.00 Methylparaben, NF 0.1800 Propylparaben, NF 0.02400 Sodium Hydroxide, N.F.* li q.s. to pH 5.5 - 6.0 Purified Water, USP q.s. ad 100.0 mL
*20% solution prepared Processing Method A portion of purified water is heated to approximately 70 C and the methylparaben and propylparaben are added while continuously mixing. Once the parabens have completely dissolved, the solution is allowed to cool to less than 35 C, and then the carbomer 934P is dispersed in the preservative solution while mixing. The pH is adjusted to pH 5.5 - 5.8 with 20% sodium hydroxide Solution.
The gel is continually stirred for approximately 20 minutes and the pH
remeasured. The sorbitol solution is added while mixing. Then the sucrose is added and mixing continued for 30 minutes. The polysorbate 80 is dissolved in a portion of purified water, the nevirapine is then added to the polysorbate 80 solution, and the mixture is homogenized for at least 40 minutes. The nevirapine/polysorbate 80 drug concentrate is thoroughly blended into the carbomer gel. The suspension is adjusted to volume or weight with purified water and blended for 30 minutes.
*20% solution prepared Processing Method A portion of purified water is heated to approximately 70 C and the methylparaben and propylparaben are added while continuously mixing. Once the parabens have completely dissolved, the solution is allowed to cool to less than 35 C, and then the carbomer 934P is dispersed in the preservative solution while mixing. The pH is adjusted to pH 5.5 - 5.8 with 20% sodium hydroxide Solution.
The gel is continually stirred for approximately 20 minutes and the pH
remeasured. The sorbitol solution is added while mixing. Then the sucrose is added and mixing continued for 30 minutes. The polysorbate 80 is dissolved in a portion of purified water, the nevirapine is then added to the polysorbate 80 solution, and the mixture is homogenized for at least 40 minutes. The nevirapine/polysorbate 80 drug concentrate is thoroughly blended into the carbomer gel. The suspension is adjusted to volume or weight with purified water and blended for 30 minutes.
Claims (3)
1. A method for preparing nevirapine hemihydrate which method comprises the steps of:
(a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt;
(b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.
(a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt;
(b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.
2. The method for preparing nevirapine hemihydrate in accordance with claim 1, wherein the separated nevirapine hemihydrate produced in step (d) is dried until the water content is between about 3.1 and 3.9% by weight.
3. A method for preparing an aqueous suspension of nevirapine hemihydrate wherein the crystal size of the nevirapine hemihydrate is pharmaceutically acceptable and remains stable over time, which method comprises the steps of:
(a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield an acid addition salt;
(b) treating the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form;
and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration;
(d) washing the separated nevirapine hemihydrate with water;
(e) optionally milling the dried nevirapine hemihydrate to obtain a particle size that is suitable for producing a pharmaceutically acceptable suspension, if the particles are not already of such size; and, (f) mixing the dried and optionally milled nevirapine hemihydrate with water, to obtain the aqueous suspension.
(a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield an acid addition salt;
(b) treating the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form;
and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration;
(d) washing the separated nevirapine hemihydrate with water;
(e) optionally milling the dried nevirapine hemihydrate to obtain a particle size that is suitable for producing a pharmaceutically acceptable suspension, if the particles are not already of such size; and, (f) mixing the dried and optionally milled nevirapine hemihydrate with water, to obtain the aqueous suspension.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5680397P | 1997-08-25 | 1997-08-25 | |
| US60/056,803 | 1997-08-25 | ||
| CA002301646A CA2301646C (en) | 1997-08-25 | 1998-08-11 | Pharmaceutical suspension comprising nevirapine hemihydrate |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002301646A Division CA2301646C (en) | 1997-08-25 | 1998-08-11 | Pharmaceutical suspension comprising nevirapine hemihydrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2617000A1 CA2617000A1 (en) | 1999-03-04 |
| CA2617000C true CA2617000C (en) | 2011-02-15 |
Family
ID=39315337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2617000A Expired - Fee Related CA2617000C (en) | 1997-08-25 | 1998-08-11 | Methods for preparing nevirapine hemihydrate and an aqueous suspension thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2617000C (en) |
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1998
- 1998-08-11 CA CA2617000A patent/CA2617000C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CA2617000A1 (en) | 1999-03-04 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20160811 |