WO2007060682A1

WO2007060682A1 - Effervescent granular formulations of antiretroviral drugs

Info

Publication number: WO2007060682A1
Application number: PCT/IN2005/000385
Authority: WO
Inventors: Venkat Subramanian Iyer; Sathya C. H. Srinivas
Original assignee: Strides Arcolab Limited
Priority date: 2005-11-28
Filing date: 2005-11-28
Publication date: 2007-05-31

Abstract

Disclosed is a unit dosage taste masked effervescent granular formulation of an antiretroviral drug filled into a sachet, which is easily administrable to children and elderly persons. The formulation comprises of an effective amount of an antiretroviral drug, an acidic agent, a basic agent which is capable of releasing carbon dioxide upon reacting with acid when comes in contact with water and other pharmaceutical additives such as a filler/diluent, a sweetening agent, a flavoring agent, a taste masking agent, a surfactant, a stabilizer and lubricants.

Description

EFFERVESCENT GRANULAR FORMULATIONS OF ANTIRETROVIRAL DRUGS

Field of the Invention This invention generally relates to granular formulations of antiretroviral drugs. More particularly, this invention relates to unit dosage taste masked effervescent granular formulations of antiretroviral drugs filled into sachets, which is easily administrable to children and elderly persons.

Background of the Invention

Antiretroviral drugs inhibit the reproduction of retroviruses-viruses composed of RNA rather than DNA. The best known of this group is HIV, human immunodeficiency virus, the causative agent of AIDS.

These inhibitors of reverse transcriptase cause chain termination when incorporated into a growing viral strand. Antiretroviral agents are used in combination for HIV postexposure prophylaxis (PEP). Agents included in this class of drugs are nucleoside reverse transcriptase inhibitors (NRTIs) (e.g. zidovudine, abacavir, didanosine, lamivudine, stavudine, zalcitabine), protease inhibitors (PIs) (e.g. indinavir, nelfmavir, ritonavir, saquinavir), nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g. delavirdine, efavirenz, nevirapine), and fusion inhibitors (e.g. enfuvirtide). Those that inhibit reverse transcriptase, act by preventing the spread of the virus to uninfected cells; whereas, protease inhibitors act at a late stage of viral replication, preventing the maturation of the viral particle to an infective form. Fusion inhibitors block HIV from entering the human immune cell by inhibiting gp41 protein, thereby disrupting structural rearrangement for the virus to fuse with healthy immune cells and preventing HIV replication.

Known arts in this area reveal several therapeutic dosage forms of the antiretroviral drugs alone or in combined forms.

United States Patent No. 5,880,106 to Ullah, et al. discloses oral dosing formulations of acid labile dideoxy purine nucleoside derivatives by finding a combination of antacid buffers effective in preventing acid hydrolysis of the nucleoside agent and providing reduced mass dosage units in the forms of convenient, palatable chewable/dispersible tablets or a dry powder sachet.

United States Patent No. 6,372,255 to Saslawski, et al. discloses a multilayer tablet dosage form for instant and prolonged release of one or more active substances comprising effervescent mixtures as disintegrating agent. Alkali metal or alkaline earth metal carbonates or bicarbonates or sodium Glycine carbonate are disclosed as effervescent mixtures.

United States Patent No. 6,420,411 to Camden, et al. discloses compounds and methods for use thereof in the treatment of cancer of viral infections by oral formulations including capsules, gels, cachets, tablets, effervescent or non- effervescent powders or tablets, powders or granules, a solution or suspension.

United States Patent No. 6,486,183 to Salhberg, et al. discloses a compound having antiretroviral activity, which can be combined with other antiretroviral agents. Also disclosed is formulations for oral administration, which may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent, as a powder or granules, as a solution or suspension.

United States Patent No. 6,498,254 to Brewer, et al. discloses pyridine and quinoline derivatives which inhibit replication of the retrovirus HIV-I, HIV-2 and human cytomegalovirus (HCMV) in appropriate unit forms of administration including oral forms such as tablets, capsules, powders, cachets, granules and solutions or suspensions. Also disclosed is water-dispersible powders or granules, which can contain the active principle mixed, e.g., with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners and/or other flavoring agents.

United States Patent No. 6,541,510 to Travis discloses a method for inhibiting the replication or proliferation of HIV within a host cell in a pharmacologically- acceptable composition, which can also be formulated for oral delivery, for e.g. in the form of capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions, emulsions^', etc. United States Patent No. 6,544,961 to St. Clair, et al. discloses a method for the treatment of an HIV infection resistant to nucleoside or non-nucleoside inhibitors comprising a combination of three active ingredients in formulations suitable for oral administration, presented as discrete units such as capsules, caplets, cachets or tablets, as a powder or granules, as a solution or a suspension in a patient pack comprising a synergistic combination of active ingredients and an information insert containing directions on the use of all three active ingredients.

United States Patent No. 6,569,463 to Patel, et al. discloses solid carriers for improved delivery of hydrophobic active ingredients in pharmaceutical compositions where the active ingredient can be a drug, a nutrient, a cosmeceutical, a diagnostic agent, a salt thereof, an isomer thereof, a derivative thereof, or a mixture thereof. Also disclosed is the pharmaceutical composition in the form of a capsule, a tablet, an ovule, a suppository, a wafer, a chewable tablet, a buccal tablet, a sublingual tablet, a quick- dissolve tablet, an effervescent tablet, a granule, a pellet, a bead, a pill, a sachet, a sprinkle, a film, a dry syrup, a reconstitutable solid, a suspension, a lozenge, a troche, an implant, a powder, a triturate, a platelet, or a strip.

Present invention' provides a novel dosage form being unit dose packing of the effervescent granular formulation of antiretroviral drugs. The formulation is stable and easy to administer to children and elderly people.

Summary of the Invention In accordance with one preferred embodiment, the present invention provides for a unit dosage effervescent granular formulation of antiretroviral drugs wherein the formulation comprises a pharmaceutically effective amount of an antiretroviral drug, an acidic agent, a basic agent and a plurality of pharmaceutical additives, the formulation devised into sachets.

In accordance with another preferred embodiment, there is provided an effervescent granular form of antiretroviral drugs wherein the effervescent granules are intended to be dispersed in water before administration. Their breakdown is ensured by release of carbon dioxide resulting from the reaction of a basic agent with the acidic agent when contacted with water. The acidic agent comprises an organic acid selected from the, group consisting of fumaric acid, tartaric acid, citric acid, any other mineral acids and mixture thereof. The basic agent comprises generally a carbonate or bicarbonate of alkali metals such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixture thereof.

In accordance with another preferred embodiment, the invention provides for an effervescent granular formulation of antiretroviral drugs wherein the formulation comprises about 5 to 90% by weight of base capable of releasing carbon dioxide upon reaction with acid which is about 2 to 95% by weight in the formulation.

In accordance with yet another preferred embodiment, the invention provides for a taste masked effervescent granular formulation comprising a combination of about 0.05% to 20% by weight of flavoring agent and bitter modifier to provide the effective taste masking of the antiretroviral drugs.

In accordance with still another preferred embodiment, the invention provides for an effervescent granular formulation of antiretroviral drugs the formulation further comprises about 0.5% to 98% by weight of diluent/fillers, about 0.2% to 15% by weight of sweetening agent, about 0.5% to 20% by weight of binder, about 0.2% to 5% by weight of coloring agent, about 0.1% to 10.0% by weight of surfactants, and about 0.05% to 5.0% by weight of stabilizers and .1% to 5% by weight of lubricants

The effervescent granular formulation according to the present invention can be prepared by conventional process, wherein the process comprises; preparing effervescent granular forms either via wet granulation method, dry granulation method, or direct mixing method.

In accordance with another preferred embodiment, the invention provides for a process for preparing an effervescent granular formulation of antiretroviral drugs employing wet granulation method wherein the process comprises; granulating acid, base and diluent either individually or in combination with pharmaceutically acceptable binders with alcoholic granulating media, subsequently it can be dried to a required level of moisture content. This granules can be mixed with active drug in a suitable blender along with other ingredients like sweetening agents, flavoring agents, taste masking agents, surfactants, stabilizers and lubricants to get uniform free flowing blend. These lubricated granules are filled in Sachets using suitable filling machine. In accordance with still another preferred embodiment, the invention provides for a process for preparing an effervescent granular formulation of antiretroviral drugs by using dry granulation method wherein the process comprises; mixing acid, base and diluents uniformly using suitable blender, then it is made into slugs using rotary compression machine, which can be deslugged by using size reducing machines like multi mill or oscillating granulator etc., these granules are then mixed with active drug in a suitable blender along with other ingredients like sweetening agents, flavoring agents, taste masking agents, surfactants, stabilizers and lubricants to get uniform free flowing blend. These lubricated granules are filled in Sachets using suitable filling machine.

In accordance with still another preferred embodiment, the invention provides for a process for preparing an effervescent granular formulation of antiretroviral drags by using compaction method, the acid, base and filler/diluent along with or without lubricants are mixed in a suitable blender and taken for compaction process individually or in combination. The flakes can be milled through multi mill or oscillating granulator to get granules. These granules are then mixed with active drug in a suitable blender along with other ingredients like sweetening agents, flavoring agents, taste masking agents, surfactants, stabilizers and lubricants to get uniform blend. These lubricated granules are filled in Sachets using suitable filling machine.

In accordance with still another preferred embodiment, the invention provides for .a process for preparing an effervescent granular formulation of antiretroviral drags by using direct granulation method, free flowing excipients can be mixed with active ingredients, acid, base, sweetening agents, flavoring agents, taste masking agents, surfactants, stabilizers and lubricants to get uniform free flowing blend. These lubricated granules are filled in Sachets using suitable filling machine.

Detailed Description of the Invention

The present invention provides an effervescent granular formulation of antiretroviral drags wherein the formulation comprises the effective amount of antiretroviral drugs, acidic agents, basic agents capable of releasing carbon dioxide upon reacting with acid in contact with water and other pharmaceutical additives such as filler/diluents, sweetening agents, flavoring agents, taste masking agents, surfactants, stabilizers and lubricants.

There are provided the effervescent .granules of antiretroviral drugs wherein the said antiretroviral drugs either individually or in combination in a therapeutically effective concentration can include lamivudine, zidovudine, stavudine, nevirapine, abacavir, didanosine, Ganciclovir, Zalcitabine, efavirenz, delaviridine, nelfinavir, ritonavir, indinavir, saquinavir, amprenavir, lopinavir and any other antiretroviral drug.

According to the present invention the effervescent granular formulation comprises drugs concentration, which may range its entire therapeutic index concentration and also maintenance dose, used individually or in combination thereof.

According to the present invention the diluents/filler used in the formulation can include cellulose derivative, lactose, maize starch, modified starch, pregelatinised starch, partially hydrolysed starch, calcium salts, magnesium salts, maltodextrin, sorbitol, mannitol, sucrose, mannose etc.

According to the present invention the sweetening agents used in the formulation can include Aspartame, sucrose, xylitol, sodium saccharine, glucose, sorbitol, glycyrrhizin etc.

According to the present invention the Bitter masking flavoring agents, used in the formulation can include lemon, orange, american ice cream, strawberry, cherry, honey, pineapple, mixed fruit, toffee, coffee, mango, licorice products and other fruit flavors, used alone or mixture thereof.

According to the present invention the coloring agents used in the formulation can include riboflavin, beta-carotene.

Lubricants used in the present invention can include calcium and magnesium salts of stearic acid, purified talc, colloidal anhydrous silica, Glycerol dibehenate etc. According to the present invention the surfactants used in the formulation can include sodium lauryl sulphate, tween 80 and spans.

According to the present invention the stabilizer used in the formulation can include butylated hydroxy toluene, butylated hydroxy anisole, sodium benzoate.

Binders like Starch derivatives, Povidone, pregelatinised starch can be used in the granulation formulation according to the present invention.

The advantage of the dosage form is unit dose which can be consumed easily any where, increased patient acceptance because of its taste masking, flavored properties and easy to administration.

According to the present invention there are provided a standard process for preparing effervescent forms of the active ingredients and pharmaceutically acceptable additives comprising steps of granulating powder, either via a wet granulation method or dry granulation method or by direct mixing method.

Preferred embodiment is further illustrated in the following examples. These examples illustrate particular embodiments of the invention and are not intended to limit the scope of the invention in any way.

Example 1

Example-2

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:

1. A unit dosage pharmaceutical formulation comprising an effective therapeutic amount of an an ti -retroviral drug, an acidic agent, a basic agent, a diluent/filler, a binder, a sweetening agent, a bitter masking flavoring agent; a surfactant; a stabilizer, a coloring agent; and a lubricant, wherein the pharmaceutical formulation is in the form of effervescent granules filled into sachets.

2. The unit dosage pharmaceutical formulation according to claim 1, wherein the said antiretroviral drug is selected from a group comprising lamivudine, zidovudine, stavudine, nevirapine, abacavir, didanosine, ganciclovir, zalcitabine, efavirenz, delaviridine, nelfinavir, ritonavir, indinavir, saquinavir, amprenavir, lopinavir etc. and mixture thereof.

3. The unit dosage pharmaceutical formulation according to claim 1, wherein the acidic agent is selected from a group comprising fumaric acid, tartaric acid, citric acid, or any other mineral acids and mixture thereof.

4. The unit dosage pharmaceutical formulation according to claim 3, wherein the formulation comprises 2 to 95% by weight of the acidic agent.

5. The unit dosage pharmaceutical formulation according to claim 1, wherein the basic agent are a carbonate or bicarbonate of alkali metals.

6. The unit dosage pharmaceutical formulation according to claim 5, wherein the carbonates or bicarbonates of alkali metals are sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixture thereof.

7. The unit dosage pharmaceutical formulation according to claim 5, wherein the formulation comprises 5 to 90% by weight of a basic agent.

8. The unit dosage pharmaceutical formulation according to claim 1, wherein said diluent/filler is selected from a group comprising cellulose derivative, lactose, maize starch, modified starch, pregelatinised starch, partially hydrolysed starch, calcium salts, magnesium salts, maltodextrin, sorbitol, tnannitol, sucrose, mannose etc.

9. The unit dosage pharmaceutical formulation according to claim 8, wherein the formulation comprises 0.5% to 98% by weight of the diluent/filler.

10. The unit dosage pharmaceutical formulation according to claim 1, wherein the binder is selected from a group comprising starch derivatives, Povidone and pregelatinised starch.

1 1. The unit dosage pharmaceutical formulation according to claim 10, wherein the formulation comprises 0.5% to 20% by weight of binder.

12. The unit dosage pharmaceutical formulation according to claim 1, wherein the sweetening agent is selected from a group comprising aspartame, sucrose, xylitol, sodium saccharine, glucose, sorbitol, glycyrrhizin etc.

13. The unit dosage pharmaceutical formulation according to claim 12, wherein the formulation comprises 0.2% to 15% by weight of sweetening agent.

14. The unit dosage pharmaceutical formulation according to claim 1, wherein the bitter masking flavoring agent is selected from a group comprising lemon, orange, American ice cream, strawberry, cherry, honey, pineapple, mixed fruit, toffee, coffee, mango, licorice products and other fruit flavors and mixture thereof.

15. The unit dosage pharmaceutical formulation according to claim 14, wherein the formulation comprises 0.05% to 20% by weight of bitter masking flavoring agents.

16. The unit dosage pharmaceutical formulation according to claim 1, wherein the surfactant is selected from a group comprising sodium lauryl sulphate, tween 80 and spans.

17. The unit dosage pharmaceutical formulation according to claim 16, wherein the formulation comprises 0.1% to 10.0% by weight of surfactants.

18. The unit dosage pharmaceutical formulation according to claim 1, wherein the stabilizer is selected form a group comprising butylated hydroxy toluene, butylated hydroxy anisole, sodium benzoate.

19. The unit dosage pharmaceutical formulation according to claim 18, wherein the formulation comprises 0.05% to 5.0% by weight of the stabilizer.

20. The unit dosage pharmaceutical formulation according to claim 1, wherein the coloring agent is riboflavin or beta-carotene.

21. The unit dosage pharmaceutical formulation according to claim 20, wherein the formulation comprises 0.2% to 5% by weight of the coloring agent.

22. The unit dosage pharmaceutical formulation according to claim 1, wherein the lubricant is selected from a group comprising calcium and magnesium salts of stearic acid, purified talc, colloidal anhydrous silica, Glycerol dibehenate etc.

23. The unit dosage pharmaceutical formulation according to claim 20, wherein the formulation comprises 0.1% to 5% by weight of lubricants.

24. The invention according to any of the preceding claims and supported by the description and the examples.