WO2014132226A1 - Formulation dispersible stable de maléate d'artérolane et de pipéraquine et procédé de préparation de celle-ci - Google Patents
Formulation dispersible stable de maléate d'artérolane et de pipéraquine et procédé de préparation de celle-ci Download PDFInfo
- Publication number
- WO2014132226A1 WO2014132226A1 PCT/IB2014/059317 IB2014059317W WO2014132226A1 WO 2014132226 A1 WO2014132226 A1 WO 2014132226A1 IB 2014059317 W IB2014059317 W IB 2014059317W WO 2014132226 A1 WO2014132226 A1 WO 2014132226A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- piperaquine
- stable dispersible
- dispersible formulation
- stable
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- 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.
- artemisinin qinghaosu
- qinghaosu a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua
- a number of its precursors, metabolites, and semi-synthetic derivatives have also been shown to possess promising antimalarial properties.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- a first aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:
- 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.
- 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.
- a stable dispersible formulation of arterolane maleate and piperaquine wherein the formulation is prepared by a dry process.
- 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 stable dispersible formulation of arterolane maleate and piperaquine comprising:
- a stable dispersible formulation of arterolane maleate and piperaquine comprising:
- a third aspect of the present invention provides a stable dispersible formulation of arterolane maleate and piperaquine comprising:
- the formulation disintegrates in water within 3 minutes, and wherein the formulation is used for the treatment of malaria.
- 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:
- formulation disintegrates in water within 3 minutes, and wherein the formulation is administered once daily for three days.
- dispenser 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.
- homogeneous dispersion 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.
- stable 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.
- amerolane maleate means the maleate salt of cis- adamantane-2-spiro-3 ' -8 ' -[[ [(2 ' -amino-2 ' -methylpropyl)amino]carbonyl] methyl] - ⁇ , 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.
- piperaquine 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 salt
- 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.
- the present invention is advantageous as it provides a simplified dosing regimen based on the age group of the patient.
- 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:
- the dosing regimen is one tablet once a day for three days;
- the dosing regimen is two tablets once a day for three days;
- 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.
- 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.
- water-dispersible celluloses are co-processed, spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium.
- 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 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-
- 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.
- 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.
- the dispersible tablet may be further coated with one or more non-functional layers comprising film-forming polymers and other coating additives.
- film-forming polymers include, but are not limited to, cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropylcellulose,
- methylcellulose carboxymethylcellulose, hydroxymethylcellulose, or mixtures thereof.
- 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.
- 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.
- Aspartame, orange flavor, and vanilla flavor were sifted through a sieve # 60 BSS.
- step 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.
- step 4 The lubricated blend of step 4 was compressed using suitable size punches to obtain compressed tablets.
- 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
- 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.
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Abstract
La présente invention concerne une formulation dispersible stable de maléate d'artérolane et de pipéraquine, la formulation présentant une intégrité structurelle améliorée et étant capable de se désintégrer rapidement dans l'eau en 3 minutes. La formulation dispersible présente un goût acceptable et laisse un résidu minimal dans la bouche. La présente invention concerne en outre un procédé pour la préparation de ladite formulation dispersible.
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AP2015008748A AP2015008748A0 (en) | 2013-02-28 | 2014-02-27 | Stable dispersible formulation of arterolane maleate and piperaquine and process of preparation thereof |
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IN587/DEL/2013 | 2013-02-28 | ||
IN587DE2013 | 2013-02-28 |
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WO2014132226A1 true WO2014132226A1 (fr) | 2014-09-04 |
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PCT/IB2014/059317 WO2014132226A1 (fr) | 2013-02-28 | 2014-02-27 | Formulation dispersible stable de maléate d'artérolane et de pipéraquine et procédé de préparation de celle-ci |
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AP (1) | AP2015008748A0 (fr) |
WO (1) | WO2014132226A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111201013A (zh) * | 2017-10-13 | 2020-05-26 | 研究三角协会 | 硫酸羟基氯喹制剂及其制备和使用方法 |
WO2022034553A1 (fr) * | 2020-08-14 | 2022-02-17 | Sun Pharmaceutical Industries Limited | Médicament combiné à dose fixe pour le traitement du paludisme |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006123314A2 (fr) * | 2005-05-18 | 2006-11-23 | Ranbaxy Laboratories Limited | Formes dosifiees stables de substances antipaludiques de spiro 1,2,4-trioxolane et de dispiro 1,2,4-trioxolane |
WO2013008218A1 (fr) | 2011-07-14 | 2013-01-17 | Ranbaxy Laboratories Limited | Formes posologiques stables d'artérolane et de pipéraquine |
-
2014
- 2014-02-27 WO PCT/IB2014/059317 patent/WO2014132226A1/fr active Application Filing
- 2014-02-27 AP AP2015008748A patent/AP2015008748A0/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006123314A2 (fr) * | 2005-05-18 | 2006-11-23 | Ranbaxy Laboratories Limited | Formes dosifiees stables de substances antipaludiques de spiro 1,2,4-trioxolane et de dispiro 1,2,4-trioxolane |
WO2013008218A1 (fr) | 2011-07-14 | 2013-01-17 | Ranbaxy Laboratories Limited | Formes posologiques stables d'artérolane et de pipéraquine |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111201013A (zh) * | 2017-10-13 | 2020-05-26 | 研究三角协会 | 硫酸羟基氯喹制剂及其制备和使用方法 |
WO2022034553A1 (fr) * | 2020-08-14 | 2022-02-17 | Sun Pharmaceutical Industries Limited | Médicament combiné à dose fixe pour le traitement du paludisme |
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