WO2014132226A1

WO2014132226A1 - Stable dispersible formulation of arterolane maleate and piperaquine and process of preparation thereof

Info

Publication number: WO2014132226A1
Application number: PCT/IB2014/059317
Authority: WO
Inventors: Harish Kumar Madan; Annamdevara Balaji; Sumit Madan; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2013-02-28
Filing date: 2014-02-27
Publication date: 2014-09-04
Anticipated expiration: 2015-08-28
Also published as: AP2015008748A0

Abstract

The present invention relates to a stable dispersible formulation of arterolane maleate and piperaquine, wherein the formulation exhibits enhanced structural integrity and is able to rapidly disintegrate in water within 3 minutes. The dispersible formulation presents acceptable taste and leaves minimal residue in the mouth. The present invention also relates to a process for the preparation of said dispersible formulation.

Description

STABLE DISPERSIBLE FORMULATION OF ARTEROLANE MALEATE AND PIPERAQUINE AND PROCESS OF PREPARATION THEREOF

Field of the Invention

Background of the Invention

The World Health Organization currently estimates that each year malaria causes

300 to 500 million infections and over 1 million deaths worldwide. Although it has been eradicated from the developed countries, malaria continues to inflict a heavy toll on the life and health in a substantial part of the world. About 40% of the world's population lives in areas where malaria is common such as Africa, Asia, Central America, Oceania, and South America. Nine out of ten malaria-related deaths occur in Sub-Saharan Africa and 86% of those occur in children under the age of 5. These children are susceptible to repeated and often serious attacks of malaria. In Africa alone, a child dies every 60 seconds from malaria. Many children who survive a serious attack of malaria develop physical and mental impairment. Low cost, commonly used therapies are becoming increasingly ineffective. In many Sub-Saharan countries, 70 percent of malaria cases are resistant to the low-cost existing anti-malarial drugs such as chloroquine and

sulphadoxine-pyrimethamine .

The discovery of artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua, was a major breakthrough in the treatment of malaria, and a number of its precursors, metabolites, and semi-synthetic derivatives have also been shown to possess promising antimalarial properties. In 2006, after artemisinin had become the treatment of choice for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of combinations of artemisinin with another antimalarial drug, to reduce the risk of resistance development. Fixed dose artemisinin combination therapies which are currently recommended by WHO for the treatment of uncomplicated falciparum malaria include: artemether + lumefantrine; artesunate + amodiaquine; artesunate + mefloquine; artesunate + sulfadoxine- pyrimethamine; dihydroartemisinin + piperaquine; and artesunate + pyronaridine tetraphosphate.

Oral tablets have been the most preferred dosage form for the administration of a wide variety of drugs; however, certain groups of patients, like pediatrics and geriatrics, face difficulty in swallowing these tablets and consequently this leads to incomplete regimens. In the case of malaria, non-compliance may even lead to the development of resistance. For such patients, dispersible formulations are the most suitable dosage forms as these combine the advantages of both dry and liquid formulations, have an acceptable taste, offer a pleasant mouth feel, and leave minimal residue in the mouth after administration.

Thus, there is a constant need for the development of a dispersible formulation based on artemisinin combination therapy which rapidly disintegrates in water and helps the patients to conveniently ingest and achieve compliance.

Dispersible tablets of artemether and lumefantrine marketed under the trade name of Coartem^® were the first artemisinin-based combination therapy developed specifically for children suffering from malaria. However, the Coartem^® tablet has to be administered in a twice daily dosage regimen based on the body weight of the child being administered the tablet. For example, for children with body weight of 5 kg to less than 15 kg, the dosing regimen includes one tablet twice a day for three days, and for children with body weight of 15 kg to less than 25 kg, the dosing regimen includes two tablets twice a day for three days. Thus, for the pediatric population suffering from malaria, there remains a need for artemisinin-based combination therapy exhibiting a simplified once daily dosing regimen.

The scientists of the present invention have now developed an orally administered dispersible formulation of a fully synthetic artemisinin-based derivative, arterolane maleate, in combination with piperaquine. This formulation is advantageous for special groups of patients who have difficulty in swallowing conventional dosage forms, particularly pediatric patients. For pediatric use, the dosing regimen of the present invention is as simple as once daily for three days. Our earlier co-pending PCT Publication No. WO 2013/008218, discloses a dry process as the preferred method for formulating an oral formulation of arterolane maleate in combination with piperaquine. The dispersible formulation of the present invention has been developed using dry processes and exhibits acceptable stability. Further, it has been surprisingly found that the dispersible formulation prepared in accordance with the present invention not only achieves rapid disintegration, but also ensures dosage uniformity by forming a homogeneous dispersion.

Summary of the Invention

The present invention provides a stable dispersible formulation of arterolane maleate and piperaquine, wherein the formulation disintegrates in water within 3 minutes. The dispersible formulation has an acceptable taste, offers a pleasant mouth feel, and leaves minimal residue in the mouth after administration. Said stable dispersible formulation is specially designed for the pediatric group of patients with a simplified dosage regimen. The present invention further provides a process for the preparation of said stable dispersible formulation.

Detailed Description of the Invention

A first aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate; and

(b) piperaquine

wherein the formulation disintegrates in water within 3 minutes.

According to one embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine, wherein the arterolane maleate and piperaquine are present in a weight ratio of about 1 : 1 to about 1 : 10.

According to another embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine, wherein arterolane maleate is present in a dose range of about 20 mg to about 80 mg and piperaquine phosphate is present in a dose range of about 150 mg to about 200 mg. According to another embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine, wherein the formulation is prepared by a dry process.

According to another embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine, wherein the formulation is prepared by a dry process, and wherein the dry process comprises direct compression or dry granulation.

A second aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate;

(b) piperaquine;

(c) one or more fillers;

(d) one or more superdisintegrants; and

(e) one or more suspending agents

wherein the formulation disintegrates in water within 3 minutes.

According to one embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) about 2% to about 15% by weight of arterolane maleate;

(b) about 15% to about 40% by weight of piperaquine;

(c) about 30% to about 70% by weight of a filler;

(d) about 5% to about 15% by weight of a superdisintegrant; and

(e) about 1% to about 10% by weight of a suspending agent.

According to another embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate;

(b) piperaquine;

(c) microcrystalline cellulose as a filler;

(d) croscarmellose as a superdisintegrant; and

(e) water-dispersible cellulose as a suspending agent. A third aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate; and

(b) piperaquine

wherein the formulation disintegrates in water within 3 minutes, and wherein the formulation is used for the treatment of malaria.

According to one embodiment of the above aspect, there is provided a stable dispersible formulation of arterolane maleate and piperaquine, wherein the formulation is used for the treatment of malaria caused by Plasmodium falciparum and Plasmodium vivax.

A fourth aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate; and

(b) piperaquine

wherein the formulation disintegrates in water within 3 minutes, and wherein the formulation is administered once daily for three days.

The term "dispersible", as used herein, means a formulation that disintegrates within 3 minutes to form a dispersion, solution, non-gritty suspension, or slurry when placed either in water or in the oral cavity.

The term "homogeneous dispersion", as used herein, means that the dispersion produced upon contact with water or saliva ensures the uniformity of arterolane maleate and piperaquine content for a reasonable period of time.

The term "stable", as used herein, means percentage degradation of both arterolane maleate and piperaquine is not more than 5% of the initial value, after storage at 30°C and 75% relative humidity for a period of three years.

The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The term "arterolane maleate", as used herein, means the maleate salt of cis- adamantane-2-spiro-3 ' -8 ' -[[ [(2 ' -amino-2 ' -methylpropyl)amino]carbonyl] methyl] - Γ , 2 ' , 4'-trioxaspiro[4.5]decane. The term further includes its individual enantiomers, diastereomers, racemates, and other isomers. The present invention comprises arterolane maleate in an amount of from about 2% to about 15% w/w of the total formulation.

The term "piperaquine", as used herein, includes piperaquine free base as well as its pharmaceutically acceptable salts. Suitable salts of piperaquine include, but are not limited to, acid addition salts such as those made with phosphoric, maleic, malonic, succinic, fumaric, malic, tartaric, citric, methylsulfonic, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, acetic, propionic, glycolic, lactic pyruvic, benzoic, carbonic, cinnamic, mandelic, methane sulfonic, ethanesulfonic, hydroxy ethane sulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2- phenoxybenzoic, and 2-acetoxybenzoic acids; and salts made with saccharin. Preferably, the salt is phosphoric acid, forming piperaquine phosphate. It further includes all individual enantiomers, diastereomers, racemates, and other isomers. The present invention comprises piperaquine as piperaquine phosphate in an amount of from about 15% to about 40% w/w of the total formulation.

The present invention comprises arterolane maleate and piperaquine in a weight ratio of about 1 : 1 to about 1 : 10.

The present invention comprises arterolane maleate (equivalent to arterolane) in a dose range of about 20 mg to about 80 mg and piperaquine phosphate in a dose range of about 150 mg to about 200 mg.

The present invention comprises arterolane maleate (equivalent to arterolane) in a unit dose of 25 mg, 37.5 mg, and 50 mg and piperaquine phosphate in a unit dose of 187.5 mg.

The present invention provides a fixed dose combination of 37.5 mg of arterolane maleate (equivalent to arterolane) and 187.5 mg of piperaquine phosphate for pediatrics with a simple dosing regimen of once daily for three days.

For pediatric patients, the present invention is advantageous as it provides a simplified dosing regimen based on the age group of the patient. In the commercially available pediatric formulation, i.e., Coartem^® tablets, the dosing regimen is based upon the body weight of patient for which there is a requirement of a weighing machine before dispensing/deciding the dosage regimen; however, the ability to weigh the patient may not be feasible every time.

The present invention provides a simplified dosing regimen based on the age group of pediatrics such as for children of age:

- 6 months to less than 2 years, the dosing regimen is one tablet once a day for three days;

- 2 years to less than 6 years, the dosing regimen is two tablets once a day for three days; and

- 6 years to less than 12 years, the dosing regimen is three tablets once a day for three days.

The dispersible formulation of the present invention comprises a filler, a superdisintegrant, and a suspending agent.

The dispersible formulation of the present invention comprises a filler in order to give sufficient bulk to the formulation and therefore facilitates the processing of the formulation. The filler is selected from the group comprising microcrystalline cellulose, calcium disulfate, calcium trisulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, mannitol, sorbitol, calcium phosphate dibasic, calcium phosphate tribasic, kaolin, calcium silicate, maltodextrin, xylitol, erythritol, sorbitol, mannitol, starch, or mixtures thereof. The dispersible formulation of the present invention comprises a filler in an amount of from about 30% to about 70% w/w of the total formulation.

The superdisintegrant is selected from the group comprising croscarmellose sodium, low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, pregelatinized starch, microcrystalline cellulose, gum, alginic acid, or mixtures thereof. The dispersible formulation of the present invention comprises a superdisintegrant in an amount of from about 5% to about 15% w/w of the total formulation.

In the present invention, the filler and superdisintegrant are present in a weight ratio of from about 1 : 1 to about 1 0. The dispersible formulation of the present invention comprises a suspending agent which helps arterolane maleate and piperaquine to remain uniformly distributed in a suspension and thus maintain content uniformity in the suspension. The suspending agent reduces the sedimentation of arterolane maleate and piperaquine, thereby ensuring the uniformity of the dose. The suspending agent is selected from the group comprising water-dispersible celluloses, propylene glycol, polyethylene glycol, glycerin, or mixtures thereof. In particular, water-dispersible celluloses are co-processed, spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium. These have been marketed under the trade names Avicel^® RC-501 (containing 7.1% to 11.9% of sodium carboxymethyl cellulose), Avicel^® RC-581 (containing 8.3% to 13.8% of sodium carboxymethyl cellulose), Avicel^® RC-591 (containing 8.3% to 13.8% of sodium carboxymethyl cellulose). Avicel^® RC-581, and Avicel^® RC-591 differ on the basis of viscosities. The dispersible formulation of the present invention comprises a suspending agent in an amount of from about 1% to about 10% w/w of the total formulation.

The dispersible formulation of the present invention further comprises

pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable excipients", as used herein, may include any physiologically inert additive used in the pharmaceutical art of dispensing.

Pharmaceutically acceptable excipients may include lubricants, binders, sweetening agents, flavoring agents, and coloring agents.

The lubricant is selected from the group comprising magnesium stearate, colloidal silicon dioxide, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, silica gel, or mixtures thereof.

The binder is selected from the group comprising methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, microcrystalline cellulose, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, carboxyvinyl polymers, or mixtures thereof.

The sweetening agent is selected from the group comprising aspartame, maltodextrin, cyclamate, acesulfame-K and its sodium and calcium salts, saccharin and its various salts, sucrose, sucralose, sorbitol, mannitol, xylitol, glucose, dextrose, fructose, or mixtures thereof.

The flavoring agent is selected from the group comprising any natural or synthetic flavoring liquids such as volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof, including, but not limited to, spearmint, peppermint, lemon, caramel, banana, vanilla, orange, grape, lime or grapefruit citric oils, apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other mint or fruit flavor essences; an aldehyde or ester such as benzaldehyde (cherry, almond), citral, a-citral (lemon, lime), neral, beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), 2-dodedenal (citrus, mandarin); or mixtures thereof.

Examples of coloring agents include, but are not limited to, any pharmaceutically acceptable natural or synthetic dyes such as red ferric oxide, titanium dioxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow, Lake of Erythrosine, Lake Ponceau, Lake Allura Red, or mixtures thereof.

The formulation of the present invention may be selected from the group consisting of tablets, pellets, pills, granules, and powder. The pellets, pills, granules, and powder can be filled into sachets, the contents of which can be dissolved/dispersed in water. The preferred formulation is a dispersible tablet. The dispersible tablet is intended to be dispersed in water, milk, or any other suitable consumable liquid prior to the administration, resulting in a homogenous dispersion. Further, the dispersible tablet may also be kept in the mouth to form a dispersion with the help of saliva.

The key feature of the dispersible tablet is fast absorption of water or complete wetting of the tablet and disintegration of the associated particles for fast dissolution. Improving the wettability is a critical step as complete wetting on contacting the aqueous medium ensures the formation of a smooth suspension quickly after dispersion of the tablet. In the present invention, dispersible tablets are prepared by a dry process. The dry process comprises direct compression or dry granulation. Dry granulation may be compaction such as roller compaction or slugging.

In another embodiment, the dispersible tablet may be further coated with one or more non-functional layers comprising film-forming polymers and other coating additives.

Examples of film-forming polymers include, but are not limited to, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropylcellulose,

methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, or mixtures thereof. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry^®, may also be used for coating.

The coating additives comprise one or more of plasticizers, glidants, opacifiers, and lubricants.

Examples of solvents used for preparing a solution/dispersion of the coating ingredients include methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.

The invention is further illustrated by the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Total weight 750.00 mg 800.00 mg 850.00 mg

Procedure:

1. Arterolane maleate, microcrystalline cellulose, microcrystalline cellulose - sodium carboxymethyl cellulose, croscarmellose sodium, and colloidal silicon dioxide were sifted through sieve # 36 BSS and piperaquine phosphate was sifted through sieve # 18 BSS.

Aspartame, orange flavor, and vanilla flavor were sifted through a sieve # 60 BSS.

3. The materials from steps 1 and 2 were blended together for 30 minutes. 4. The blend of step 3 was lubricated with magnesium stearate.

5. The lubricated blend of step 4 was compressed using suitable size punches to obtain compressed tablets.

Disintegration Data

Three batches of six tablets, each prepared according to the formulation of Example 2, were tested for disintegration using BP Disintegration apparatus. The results of the disintegration tests are presented in Table 1.

Table 1: Disintegration Times

In-vitro Dissolution Data

In-vitro drug release from the tablets prepared according to Example 2 was determined for dissolution of arterolane maleate in USP type II apparatus at 75 rpm, in 900 mL of pH 4.5 acetate buffer with 2% tween 80 for 45 minutes. Similarly, in-vitro drug release from the tablets prepared according to Example 2,was determined for dissolution of piperaquine phosphate in USP type II apparatus at 75 rpm, in 900 mL of 0.01 N hydrochloride for 45 minutes. The results of the dissolution study are presented in Table 2. Table 2: In-vitro Drug release (% w/w) at 45 minutes

Stability Data

The tablets prepared according to Example 2 were stored at 30°C ± 2°C and 75% ± 5% relative humidity for a period of 36 months, and then analyzed for arterolane and piperaquine contents and related substances using validated in-house HPLC analytical method. The results of the analysis are represented in Table 3 and Table 4.

Table 3: Results of the Stability Study for Arterolane Maleate

Table 4: Results of the Stability Study for Piperaquine Phosphate

Claims

We Claim:

1. A stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate; and

(b) piperaquine

wherein the formulation disintegrates in water within 3 minutes.

2. The stable dispersible formulation according to claim 1, wherein arterolane maleate and piperaquine are present in a weight ratio from about 1 : 1 to about 1 : 10.

3. The stable dispersible formulation according to claim 1, wherein arterolane maleate is present in a dose range of about 20 mg to about 80 mg and piperaquine phosphate is present in a dose range of about 150 mg to about 200 mg.

4. The stable dispersible formulation according to claim 1, wherein the formulation is prepared by a dry process.

5. The stable dispersible formulation according to claim 4, wherein the dry process comprises direct compression or dry granulation.

6. The stable dispersible formulation according to claim 1, further comprising:

(a) one or more fillers;

(b) one or more superdisintegrants;and

(c) one or more suspending agents.

7. The stable dispersible formulation according to claim 6, wherein the formulation comprises:

(a) about 2% to about 15% by weight of arterolane maleate;

(b) about 15% to about 40% by weight of piperaquine;

(c) about 30% to about 70% by weight of a filler;

(d) about 5% to about 15% by weight of a superdisintegrant; and

(e) about 1% to about 10% by weight of a suspending agent.

8. The stable dispersible formulation according to claim 6, wherein the filler is selected from the group comprising microcrystalline cellulose, calcium disulfate, calcium trisulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, mannitol, sorbitol, calcium phosphate dibasic, calcium phosphate tribasic, kaolin, calcium silicate, maltodextrin, xylitol, erythritol, sorbitol, mannitol, starch, or mixtures thereof.

9. The stable dispersible formulation according to claim 6, wherein the

superdisintegrant is selected from the group comprising croscarmellose sodium, low- substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, pregelatinized starch, microcrystalline cellulose, gum, alginic acid, or mixtures thereof.

10. The stable dispersible formulation according to claim 6, wherein the suspending agent is selected from the group comprising water-dispersible celluloses, propylene glycol, polyethylene glycol, glycerin, or mixtures thereof.

11. The stable dispersible formulation according to claim 1, wherein the formulation is selected from the group consisting of tablets, pellets, pills, granules, and powder.

12. The stable dispersible formulation according to claim 11, wherein the formulation is a tablet.

13. The stable dispersible formulation according to claim 6, wherein the formulation further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of lubricants, binders, sweetening agents, flavoring agents, and coloring agents.

14. A method for treating malaria, the method comprising administering a stable dispersible formulation of arterolane maleate and piperaquine comprising:

(a) arterolane maleate; and

(b) piperaquine

wherein the formulation disintegrates in water within 3 minutes.

15. The method for treating malaria according to claim 14, wherein the formulation is administered once daily for three days.