EP2563341A1 - Pharmaceutical compositions inducing synergistic effect - Google Patents

Pharmaceutical compositions inducing synergistic effect

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Publication number
EP2563341A1
EP2563341A1 EP11720903A EP11720903A EP2563341A1 EP 2563341 A1 EP2563341 A1 EP 2563341A1 EP 11720903 A EP11720903 A EP 11720903A EP 11720903 A EP11720903 A EP 11720903A EP 2563341 A1 EP2563341 A1 EP 2563341A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
domperidone
dexlansoprazole
range
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11720903A
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German (de)
French (fr)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2563341A1 publication Critical patent/EP2563341A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl

Definitions

  • the present invention relates to a pharmaceutical combination comprising dexlansoprazole and domperidone, and use of said combination in the treatment of acid-related gastrointestinal disturbances, particularly in the treatment of diseases related with gastroesophageal reflux.
  • Gastroesophageal reflux disease is a common problem though it may present various symptoms.
  • Gastroesophageal reflux disease may lead to serious complications such as vomiting, insufficient weight gain, dysphagia, abdominal and substernal ache, esophagitis and respiratory diseases. This disease is seen in approximately 20% of adults and it results in development of barrett, then esophagus cancer in the long term if not treated.
  • the first step in the treatment of the disease is lifestyle changes. However, only patients with mild symptoms can be relieved by these changes. This has created the need to increase the number of the studies in order to provide effective and reliable treatment.
  • Proton pump inhibitors are the most potent agents in the treatment of reflux disease. Proton pump inhibitors have an inhibitory effect on gastric acid secretion in the treatment of gastroesophageal reflux disease.
  • Dexlansoprazole (Formula I), which is a proton pump inhibitor, is R-enantiomer of lansoprazole.
  • Dexlansoprazole has the chemical structure of (i?)-2-[[3-methyl-4-(2,2,2-trifluoroethoxy) -2-pyridinyl]methylsulphinyl)-lH-benzimidazole.
  • Domperidone which is a prokinetic drug disclosed in the patent numbered US 4,066,772, contributes to alleviate gastroesophageal reflux disease by increasing lower esophageal sphincter (LES) pressure, strengthening the peristaltic activity in esophagus and accelerating stomach discharge.
  • Domperidone has the chemical structure of 5-chloro-l- ⁇ l-[3-(2- oxobenzimidazoline-l-yl)propyl) -4- piperidyl ⁇ benzimidazoline-2-one and it is illustrated as in Formula II below:
  • the combination therapy utilizing the active agents dexlansoprazole and domperidone together induces synergistic effect in the treatment of acid-related gastrointestinal disturbances, particularly in the treatment of diseases related to gastroesophageal reflux.
  • the inventors have observed that a far more superior therapeutic benefit than expected is gained in the case that dexlansoprazole and domperidone are used in combination.
  • use of dexlansoprazole and domperidone in combination is more effective than the treatments comprising the use of dexlansoprazole or domperidone alone.
  • dexlansoprazole and domperidone combination is an effective alternative for cases where the treatments comprising the use of these active agents alone remain incapable.
  • this combination developed in scope of the present invention allows use of the active agents at lower doses than the cases that the two active agents are used alone for the same therapeutic response.
  • the side effects are minimized with the help of use of the active agents at lower doses.
  • the pharmaceutical combinations of the present invention comprise oral, enteral, parenteral (hypodermic, intramuscular, intravaneous) dosage forms.
  • the dosage forms according to the present invention are preferably oral dosage forms and they can be in solid dosage forms such as tablet; orally disintegrating tablet; enteric coated tablet; film coated tablet; modified release tablets such as constant release tablet, prolonged release tablet, delayed release tablet; fast soluble tablet; effervescent tablet; micro tablet; pellets; modified release pellets such as constant release pellet, prolonged release pellet, delayed release pellet; effervescent granule, fast soluble powder mixture or dry powder mixture for syrup preparation, dragee, cachet, capsule or in liquid forms such as suspension.
  • solid dosage forms such as tablet; orally disintegrating tablet; enteric coated tablet; film coated tablet; modified release tablets such as constant release tablet, prolonged release tablet, delayed release tablet; fast soluble tablet; effervescent tablet; micro tablet; pellets; modified release pellets such as constant release pellet, prolonged release pellet, delayed release pellet; effervescent granule, fast soluble powder mixture or dry powder mixture for syrup preparation, dragee, cachet, capsule or in liquid forms such as suspension.
  • compositions of the present invention comprise various pharmaceutically acceptable excipients in addition to pharmaceutically effective amounts of dexlansoprazole and domperidone.
  • the amount of dexlansoprazole used in the formulations of the present invention is in the range of 5 mg to 180 mg, preferably in the range of 10 mg to 120 mg, more preferably in the range of 15 mg to 60 mg, and the amount of domperidone is in the range of 0.25 mg to 100 mg, preferably in the range of 1 mg to 60 mg, more preferably in the range of 5 to 15 mg.
  • D(10) particle size of the active agents used in the formulations of the present invention is smaller than 50 micron; D(50) particle size is smaller than 100 micron; D(90) particle size is smaller than 200 micron.
  • the term "D(10) particle size” used in this text refers to the particle size of 10% of active agent particles by volume; the term “D(50) particle size” refers to the particle size of 50% of active agent particles by volume; the term “D(90) particle size” refers to the particle size of 90% of active agent particles by volume.
  • the pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from the group comprising pH adjusters, stabilizing agents, diluents, binders, coating materials developed to provide various release characteristics, disintegrants, anti-adhesive agents, plasticizers, rate controlling agents, filling materials, glidants, coloring agents, aqueous or non-aqueous solvents or combinations thereof.
  • the stabilizing agents that can be used in the formulations of the present invention can be selected from the group comprising basic substances such as calcium carbonate, dibasic calcium phosphate dihydrate, calcium sulphate anhydrous, calcium sulphate dihydrate, magnesium oxide, magnesium carbonate, magnesium silicate, magnesium sulphate, potassium bicarbonate, potassium hydroxide, dibasic potassium phosphate, sodium hydroxide, sodium bicarbonate, sodium carbonate, dibasic sodium phosphate, tribasic sodium phosphate, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium polyphosphate, potassium polyphosphate, sodium acetate, calcium acetate, potassium metaphosphate, calcium glycerophosphate, calcium lactate and calcium bicarbonate or combinations thereof.
  • Total amount of the stabilizing agent in the formulations of the present invention is in the range of 1% to 30% by weight.
  • the diluents that can be used in the formulations of the present invention can be selected from the group comprising calcium carbonate, calcium phosphate-dibasic, calcium phosphate- tribasic, calcium sulphate, microcrystalline cellulose, silicified microcrystalline cellulose, powderized cellulose and derivatives thereof, dextrates, dextrines, dextrose excipients, fructose, kaoline, lactitol, lactose, mannitol, sorbitol, starch and derivatives thereof, sucrose, compressed sugar, powdered sugar or combinations thereof.
  • Total amount of the diluent in the formulations of the present invention is in the range of 10% to 50% by weight.
  • the pH agents that can be used in the formulations of the present invention can be selected from the group comprising magnesium oxide, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, precipitated calcium carbonate, cellulose derivatives comprising powdered cellulose and other substances.
  • the pH agents can optionally be used in combination with the stabilizing agents in scope of the present invention.
  • Total amount of the pH agent in the formulation of the present invention is in the range of 1% to 30% by weight.
  • the binders that can be used in the formulations of the present invention can be selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, acacia, alginate derivatives, hydroxypropyl propyl cellulose, carboxymethylcellulose sodium, compressed sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose and pregelatinized starch or combinations thereof.
  • Total amount of the binder in the formulation of the present invention is in the range of 1% to 10% by weight.
  • the filling materials that can be used in the formulations of the present invention can be selected from the group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol, and lactitol or combinations thereof.
  • the enteric coating materials that can be used in the formulations of the present invention can be selected from the group comprising methacrylic copolymers such as methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/ methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, triethyl citrate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof. It can also comprise other additives along with the polymers counted as enteric coating materials. Talc and titanium dioxide can be given as examples of these additives. Total amount of enteric coating material in the compositions of the present invention is in the range of 1% to 30% by weight.
  • the disintegrants that can be used in the compositions of the present invention can be selected from the group comprising substances such as starch, starch sodium glycolate, croscarmellose sodium, crospovidone, alginate derivatives, carboxymethylcellulose sodium and guar gum or combinations thereof.
  • Total amount of the disintegrant in the compositions of the present invention is in the range of 0.5% to 15% by weight.
  • the lubricants that can be used in the compositions of the present invention can be selected from the group comprising substances such as stearate derivatives such as magnesium stearate, sodium stearil fumarate, calcium stearate, zinc stearate; polyethylene glycol, talc, hydrogenated castor oil, silica, colloidal silica, corn starch, calcium silicate, magnesium silicate and silicon hydrogel or combinations thereof.
  • Total amount of the lubricant in the compositions of the present invention is in the range of 0.1% to 5% by weight.
  • the plasticizers that can be used in the compositions of the present invention can be selected from the group comprising dibutyl sebacate, polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acidified monoglyceride, acetyl tributyl citrate, triacetine, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oil, oleic acid, castor oil, maize oil, camphor, glycerol and sorbitol polyethylene glycols, propylene glycol, glycerols, glycerides, fractionated coconut oil and castor oil, citric acid ester, phthalic acid or sebacic acid or combinations thereof. Total amount of the plasticizer in the composition is in the range of 1% to 20% by weight.
  • compositions of the present invention can optionally be formulated such that they can provide various release characteristics, for instance prolonged, delayed, constant release.
  • the rate controlling agents that can be used to determine release characteristics of the formulations can be selected from the group comprising substances such as cellulosic polymers such as ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxy methyl cellulose, hydroxyl methylcellulose and hydroxyethyl cellulose; wax; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; cellulose acetate trimellitate; methacrylic acid polymers such as Eudragit RL and RS; polymethacrylates; carboxymethylcellulose sodium; carboxymethyl cellulose calcium; polyacrilic acid; polyethylene glycol; polyethylene oxide; carrageenan; cellulose acetate; zein; carbohydrate gums; polyuronic acid salts; cellulose ethers and acrylic acid polymers or combinations thereof.
  • Total amount of the rate controlling agent in the compositions of the present invention is in the range of 10% to 50% by weight.
  • the aqueous or nonaqueous solvents that can be used in the formulation of the present invention can be selected from the group comprising solvents such as ethanol, methanol, acetone, isopropanol, dichloromethane and water or combinations thereof.
  • the glidants that can be used in the formulation of the present invention can be selected from the group comprising substances such as colloidal silicon dioxide, corn starch, talc, calcium silicate and magnesium silicate or combinations thereof.
  • the coloring agents that can be used in the formulation of the present invention can be selected from the group comprising iron oxide and its derivatives such as red iron oxide, yellow iron oxide; lacquer paint and pharmaceutically acceptable colorants or combinations thereof.
  • compositions to be produced according to the present invention can be prepared such that they comprise the active agents dexlansoprazole and domperidone in separate dosage forms or in a single dosage form, and they can be used simultaneously, sequentially or separately.
  • the active agents are administered separately.
  • the essential factor to obtain good results in pharmacotherapy is patient's compliance with the instructions. Therefore, administration of two or more different dosage forms to the patient does not yield satisfactory results most of the time.
  • the present invention provides new dosage forms formulated in a single dosage form and comprising dexlansoprazole and domperidone together as the active agent. It has been seen that a more effective treatment is provided with the combination of the present invention by formulating dexlansoprazole and domperidone in a single dosage form.
  • an advantage of the invention is that it enhances the adaptation of the patients to the treatment by combining the active agents in a single dosage form.
  • single dosage form refers to formulating the active agents and the excipients together and combining them in a single dosage form as well as formulating the active agents separately as different dosage forms and combining them in a single dosage form.
  • the inventors has unexpectedly observed that there is a positive development in the stability profile of the combined dosage form which was developed in scope of the present invention and obtained by formulating the two active agents separately and combining the unit dosage forms obtained this way in a single dosage form.
  • These dosage forms produced according to the present invention homogenously disperse in gastrointestinal tract and they are transposed to the intestines from the stomach. In this way, it is ensured that the active agents are dispersed effectively in the stomach and therefore, the efficiency and bioavailability of the combined medicament is enhanced.
  • the unit dosage forms according to the present invention can be in physical forms comprising active agent on a pharmaceutically effective amount and excipients such as tablets, micro tablets, coated tablets, effervescent tablets, soluble tablets, pellets, granules, powders, and these unit dosage forms can optionally be coated with protective coating, enteric coating, coloring coating, film coating and/or various coatings aimed to modify release characteristics.
  • the combined dosage forms preferred according to the present invention are obtained by combining independent unit dosage forms selected from the ones listed above that comprise dexlansoprazole and domperidone on pharmaceutically effective amounts preferably in a capsule.
  • the unit dosage forms can optionally be coated with protective coating, enteric coating, film coating, coloring coating and/or different coatings so as to provide various release characteristics.
  • the unit dosage forms of dexlansoprazole according to the present invention can optionally be formulated to be delayed release while the unit dosage forms of domperidone can optionally be formulated to be constant release.
  • the unit dosage forms of present invention comprising domperidone on pharmaceutically acceptable amounts are preferably in granule, powder or pellet form while the unit dosage form comprising dexlansoprazole is preferably in micro tablet form.
  • the unit dosage forms of the present invention are formulated according to the characteristics of the active agent they comprise.
  • pharmaceutically acceptable excipients comprised in separate dosage forms and their amounts can be identical or different.
  • the pellet, granule or powder compositions of domperidone according to the present invention can comprise effective amounts of domperidone and one or more pharmaceutically acceptable excipients described in detail above.
  • the unit dosage forms comprising domperidone can be produced by any method in the prior art.
  • the method preferred to be used in production of powder compositions of domperidone of the present invention is preferably dry mixing wherein said method comprises mixing domperidone on a pharmaceutically effective amount, at least one pharmaceutically acceptable filling material, at least one lubricant and optionally at least another excipient.
  • Domperidone pellets which is another unit dosage form preferred according to the present invention, are preferably constant release pellets and preferably produced by the following method:
  • Domperidone and a pharmaceutically acceptable diluent or some part of the diluent mixture are mixed dry; the coloring agent and the filling material are added into the mixture and they are all mixed again,
  • the dry active agent mixture obtained in the first step is added into the wet diluent granules obtained, they are mixed and pellets are prepared of this mixture,
  • the pellets obtained are coated with the solution prepared by dissolving the rate controlling agent in a suitable solvent.
  • micro tablets of dexlansoprazole preferred according to the present invention are composed of a tablet core comprising dexlansoprazole on an effective amount, at least one pharmaceutically acceptable disintegrants, at least one binder, at least one stabilizing agent, at least one rate controlling agent and optionally at least another excipient; a sub-coat on the core; an enteric coat on the sub-coat and optionally a coloring coat.
  • the stabilizing agents to be used in the micro tablet composition of dexlansoprazole and their amounts are selected such that pH of the composition is at a level to provide minimum degradation of dexlansoprazole.
  • the amount preferred is in the range of 1% to 50%, preferably in the range of 1% to 40%, more preferably in the range of 1% to 30% with respect to weight of the core of the unit dosage form comprising dexlansoprazole.
  • the stabilizing agent used in micro tablets of dexlansoprazole of the present invention can preferably be a magnesium salt, for instance magnesium oxide, magnesium carbonate, magnesium silicate and/or magnesium sulphate.
  • the production method for production of the micro tablets of domperidone of the present invention is preferably wet granulation and it comprises the following steps:
  • a characteristic feature of the production method given above is that the pharmaceutically acceptable excipient in the second step of the method is a stabilizing agent.
  • a characteristic feature of the production method given above is that the mixing time of the lubricant given in the fourth step of the method is in the range of 1 to 20 minutes, preferably in the range of 1 to 10 minutes.
  • the compression force required for compressing micro tablets as given in the fifth step of the method is in the range of 10 to 300 kN, preferably in the range of 10 to 200 kN.
  • micro tablets comprising dexlansoprazole are mixed with unit dosage forms of the present invention comprising domperidone on pharmaceutically effective amounts and they are preferably filled into a capsule made of soft gelatin.
  • unit dosage forms of the present invention comprising domperidone on pharmaceutically effective amounts and they are preferably filled into a capsule made of soft gelatin.
  • Example 1 Film Coated Tablet Composition 25 mg dexlansoprazole and 5 mg domperidone are taken as active agents. The combination of dexlansoprazole and domperidone is granulated with pharmaceutically acceptable excipients. The granules are dried and then sieved under appropriate humidity and temperature conditions. Tablets are compressed from the obtained final product in an appropriate tablet compressing machine. Optionally, tablets can be film coated.
  • Example 2. Combine Dosage Form-I
  • enteric coated micro tablet composition comprising dexlansoprazole so as to be produced according to the formulation given above is as follows:
  • the mixture composed of dexlansoprazole, at least one disintegrant and magnesium oxide agent is granulated by a granulation solution obtained by mixing a pharmaceutically acceptable binder and solvent; the granules are dried and then sieved.
  • the rate controlling agent is added into the garnules obtained and the blend is mixed.
  • the lubricant is added into the mixture and the blend is mixed for 5 minutes.
  • Micro tablets are compressed of the final mixture by imposing 1-300 kN of compression force.
  • micro tablets are coated with subcoating first, then with enteric coating and lastly with coloring coating.
  • the dry active agent mixture is added into the wet diluent granules obtained in the first step; they are mixed and pellets are obtained.
  • IV. The pellets obtained are coated with a solution prepared by dissolving the rate controlling agent in a suitable solvent.
  • Dexlansoprale micro tablets and domperidone pellets produced according to the production methods and the formulation given above are combined preferably in a capsule made of soft gelatin.
  • micro tablet compositions of dexlansoprazole given in examples 3 and 4 are produced according to the production method given in example 2.
  • micro tablets of dexlansoprazole and the powder compositions of domperidone obtained this way are combined in preferably a capsule made of soft gelatin.

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Abstract

The present invention relates to a pharmaceutical composition comprising dexlansoprazole and domperidone and use of said composition in the treatment of acid-related gastrointestinal disturbances, particularly in the treatment of diseases related with gastroesophageal reflux.

Description

PHARMACEUTICAL COMPOSITIONS INDUCING SYNERGISTIC EFFECT
Field of the Invention
The present invention relates to a pharmaceutical combination comprising dexlansoprazole and domperidone, and use of said combination in the treatment of acid-related gastrointestinal disturbances, particularly in the treatment of diseases related with gastroesophageal reflux.
Background of the Invention
Gastroesophageal reflux disease (GERD) is a common problem though it may present various symptoms.
Gastroesophageal reflux disease may lead to serious complications such as vomiting, insufficient weight gain, dysphagia, abdominal and substernal ache, esophagitis and respiratory diseases. This disease is seen in approximately 20% of adults and it results in development of barrett, then esophagus cancer in the long term if not treated.
The first step in the treatment of the disease is lifestyle changes. However, only patients with mild symptoms can be relieved by these changes. This has created the need to increase the number of the studies in order to provide effective and reliable treatment.
Proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole) are the most potent agents in the treatment of reflux disease. Proton pump inhibitors have an inhibitory effect on gastric acid secretion in the treatment of gastroesophageal reflux disease. Dexlansoprazole (Formula I), which is a proton pump inhibitor, is R-enantiomer of lansoprazole. Dexlansoprazole has the chemical structure of (i?)-2-[[3-methyl-4-(2,2,2-trifluoroethoxy) -2-pyridinyl]methylsulphinyl)-lH-benzimidazole.
(I) Nevertheless, there are a limited number of studies indicating the positive effect that can be obtained as a result of adding prokinetic drugs such as domperidone, cisapride, mosapride to the treatment.
Domperidone, which is a prokinetic drug disclosed in the patent numbered US 4,066,772, contributes to alleviate gastroesophageal reflux disease by increasing lower esophageal sphincter (LES) pressure, strengthening the peristaltic activity in esophagus and accelerating stomach discharge. Domperidone has the chemical structure of 5-chloro-l-{l-[3-(2- oxobenzimidazoline-l-yl)propyl) -4- piperidyl}benzimidazoline-2-one and it is illustrated as in Formula II below:
(Π)
None of prokinetic medicaments can avail in the treatment of GERD when they are utilized alone since they cannot affect pathological acid amount in distal esophagus (time spent below pH 4) if used alone. Their addition to acid-inhibitor treatment of patients with nausea along with reflux symptoms and patients with delayed stomach discharge results in more effective treatments.
When the prior art is taken into consideration, it is seen that there is need for effective pharmaceutical combinations so as to be used in the treatment of acid-related gastrointestinal disorders, particularly in the treatment of diseases related to gastroesophageal reflux.
Detailed Explanation of the Invention
In the present invention, it has been found that the combination therapy utilizing the active agents dexlansoprazole and domperidone together induces synergistic effect in the treatment of acid-related gastrointestinal disturbances, particularly in the treatment of diseases related to gastroesophageal reflux. The inventors have observed that a far more superior therapeutic benefit than expected is gained in the case that dexlansoprazole and domperidone are used in combination. In addition, it has been seen in the present invention that use of dexlansoprazole and domperidone in combination is more effective than the treatments comprising the use of dexlansoprazole or domperidone alone. Moreover, dexlansoprazole and domperidone combination is an effective alternative for cases where the treatments comprising the use of these active agents alone remain incapable.
In another aspect, this combination developed in scope of the present invention allows use of the active agents at lower doses than the cases that the two active agents are used alone for the same therapeutic response. Thus, the side effects are minimized with the help of use of the active agents at lower doses.
The pharmaceutical combination of the present invention is more advantageous than known compositions in terms of the fact that;
• dexlansoprazole and domperidone combination induces synergistic effect,
· it presents no negative drug interaction, and
• it enables to minimize the potential side effects.
The pharmaceutical combinations of the present invention comprise oral, enteral, parenteral (hypodermic, intramuscular, intravaneous) dosage forms.
The dosage forms according to the present invention are preferably oral dosage forms and they can be in solid dosage forms such as tablet; orally disintegrating tablet; enteric coated tablet; film coated tablet; modified release tablets such as constant release tablet, prolonged release tablet, delayed release tablet; fast soluble tablet; effervescent tablet; micro tablet; pellets; modified release pellets such as constant release pellet, prolonged release pellet, delayed release pellet; effervescent granule, fast soluble powder mixture or dry powder mixture for syrup preparation, dragee, cachet, capsule or in liquid forms such as suspension.
The pharmaceutical compositions of the present invention comprise various pharmaceutically acceptable excipients in addition to pharmaceutically effective amounts of dexlansoprazole and domperidone.
The amount of dexlansoprazole used in the formulations of the present invention is in the range of 5 mg to 180 mg, preferably in the range of 10 mg to 120 mg, more preferably in the range of 15 mg to 60 mg, and the amount of domperidone is in the range of 0.25 mg to 100 mg, preferably in the range of 1 mg to 60 mg, more preferably in the range of 5 to 15 mg.
D(10) particle size of the active agents used in the formulations of the present invention is smaller than 50 micron; D(50) particle size is smaller than 100 micron; D(90) particle size is smaller than 200 micron.
The term "D(10) particle size" used in this text refers to the particle size of 10% of active agent particles by volume; the term "D(50) particle size" refers to the particle size of 50% of active agent particles by volume; the term "D(90) particle size" refers to the particle size of 90% of active agent particles by volume. The pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from the group comprising pH adjusters, stabilizing agents, diluents, binders, coating materials developed to provide various release characteristics, disintegrants, anti-adhesive agents, plasticizers, rate controlling agents, filling materials, glidants, coloring agents, aqueous or non-aqueous solvents or combinations thereof. The stabilizing agents that can be used in the formulations of the present invention can be selected from the group comprising basic substances such as calcium carbonate, dibasic calcium phosphate dihydrate, calcium sulphate anhydrous, calcium sulphate dihydrate, magnesium oxide, magnesium carbonate, magnesium silicate, magnesium sulphate, potassium bicarbonate, potassium hydroxide, dibasic potassium phosphate, sodium hydroxide, sodium bicarbonate, sodium carbonate, dibasic sodium phosphate, tribasic sodium phosphate, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium polyphosphate, potassium polyphosphate, sodium acetate, calcium acetate, potassium metaphosphate, calcium glycerophosphate, calcium lactate and calcium bicarbonate or combinations thereof. Total amount of the stabilizing agent in the formulations of the present invention is in the range of 1% to 30% by weight.
The diluents that can be used in the formulations of the present invention can be selected from the group comprising calcium carbonate, calcium phosphate-dibasic, calcium phosphate- tribasic, calcium sulphate, microcrystalline cellulose, silicified microcrystalline cellulose, powderized cellulose and derivatives thereof, dextrates, dextrines, dextrose excipients, fructose, kaoline, lactitol, lactose, mannitol, sorbitol, starch and derivatives thereof, sucrose, compressed sugar, powdered sugar or combinations thereof. Total amount of the diluent in the formulations of the present invention is in the range of 10% to 50% by weight.
The pH agents that can be used in the formulations of the present invention can be selected from the group comprising magnesium oxide, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, precipitated calcium carbonate, cellulose derivatives comprising powdered cellulose and other substances. The pH agents can optionally be used in combination with the stabilizing agents in scope of the present invention. Total amount of the pH agent in the formulation of the present invention is in the range of 1% to 30% by weight.
The binders that can be used in the formulations of the present invention can be selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methylcellulose, acacia, alginate derivatives, hydroxypropyl propyl cellulose, carboxymethylcellulose sodium, compressed sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose and pregelatinized starch or combinations thereof. Total amount of the binder in the formulation of the present invention is in the range of 1% to 10% by weight. The filling materials that can be used in the formulations of the present invention can be selected from the group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol, and lactitol or combinations thereof.
The enteric coating materials that can be used in the formulations of the present invention can be selected from the group comprising methacrylic copolymers such as methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/ methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, triethyl citrate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof. It can also comprise other additives along with the polymers counted as enteric coating materials. Talc and titanium dioxide can be given as examples of these additives. Total amount of enteric coating material in the compositions of the present invention is in the range of 1% to 30% by weight.
The disintegrants that can be used in the compositions of the present invention can be selected from the group comprising substances such as starch, starch sodium glycolate, croscarmellose sodium, crospovidone, alginate derivatives, carboxymethylcellulose sodium and guar gum or combinations thereof. Total amount of the disintegrant in the compositions of the present invention is in the range of 0.5% to 15% by weight.
The lubricants that can be used in the compositions of the present invention can be selected from the group comprising substances such as stearate derivatives such as magnesium stearate, sodium stearil fumarate, calcium stearate, zinc stearate; polyethylene glycol, talc, hydrogenated castor oil, silica, colloidal silica, corn starch, calcium silicate, magnesium silicate and silicon hydrogel or combinations thereof. Total amount of the lubricant in the compositions of the present invention is in the range of 0.1% to 5% by weight.
The plasticizers that can be used in the compositions of the present invention can be selected from the group comprising dibutyl sebacate, polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acidified monoglyceride, acetyl tributyl citrate, triacetine, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oil, oleic acid, castor oil, maize oil, camphor, glycerol and sorbitol polyethylene glycols, propylene glycol, glycerols, glycerides, fractionated coconut oil and castor oil, citric acid ester, phthalic acid or sebacic acid or combinations thereof. Total amount of the plasticizer in the composition is in the range of 1% to 20% by weight.
The compositions of the present invention can optionally be formulated such that they can provide various release characteristics, for instance prolonged, delayed, constant release. The rate controlling agents that can be used to determine release characteristics of the formulations can be selected from the group comprising substances such as cellulosic polymers such as ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxy methyl cellulose, hydroxyl methylcellulose and hydroxyethyl cellulose; wax; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; cellulose acetate trimellitate; methacrylic acid polymers such as Eudragit RL and RS; polymethacrylates; carboxymethylcellulose sodium; carboxymethyl cellulose calcium; polyacrilic acid; polyethylene glycol; polyethylene oxide; carrageenan; cellulose acetate; zein; carbohydrate gums; polyuronic acid salts; cellulose ethers and acrylic acid polymers or combinations thereof. Total amount of the rate controlling agent in the compositions of the present invention is in the range of 10% to 50% by weight. The aqueous or nonaqueous solvents that can be used in the formulation of the present invention can be selected from the group comprising solvents such as ethanol, methanol, acetone, isopropanol, dichloromethane and water or combinations thereof.
The glidants that can be used in the formulation of the present invention can be selected from the group comprising substances such as colloidal silicon dioxide, corn starch, talc, calcium silicate and magnesium silicate or combinations thereof.
The coloring agents that can be used in the formulation of the present invention can be selected from the group comprising iron oxide and its derivatives such as red iron oxide, yellow iron oxide; lacquer paint and pharmaceutically acceptable colorants or combinations thereof.
The compositions to be produced according to the present invention can be prepared such that they comprise the active agents dexlansoprazole and domperidone in separate dosage forms or in a single dosage form, and they can be used simultaneously, sequentially or separately.
In most of the treatments suggested for combined use of various active agents, the active agents are administered separately. However, the essential factor to obtain good results in pharmacotherapy is patient's compliance with the instructions. Therefore, administration of two or more different dosage forms to the patient does not yield satisfactory results most of the time.
At this point, the present invention provides new dosage forms formulated in a single dosage form and comprising dexlansoprazole and domperidone together as the active agent. It has been seen that a more effective treatment is provided with the combination of the present invention by formulating dexlansoprazole and domperidone in a single dosage form.
In this aspect, an advantage of the invention is that it enhances the adaptation of the patients to the treatment by combining the active agents in a single dosage form. The term "single dosage form" refers to formulating the active agents and the excipients together and combining them in a single dosage form as well as formulating the active agents separately as different dosage forms and combining them in a single dosage form.
The inventors has unexpectedly observed that there is a positive development in the stability profile of the combined dosage form which was developed in scope of the present invention and obtained by formulating the two active agents separately and combining the unit dosage forms obtained this way in a single dosage form.
These dosage forms produced according to the present invention homogenously disperse in gastrointestinal tract and they are transposed to the intestines from the stomach. In this way, it is ensured that the active agents are dispersed effectively in the stomach and therefore, the efficiency and bioavailability of the combined medicament is enhanced.
It is advantageous to prepare the active agents separately as unit dosage forms having different physical properties and content since this also enables to produce the active agents such that they have different release characteristics than each other. The unit dosage forms according to the present invention can be in physical forms comprising active agent on a pharmaceutically effective amount and excipients such as tablets, micro tablets, coated tablets, effervescent tablets, soluble tablets, pellets, granules, powders, and these unit dosage forms can optionally be coated with protective coating, enteric coating, coloring coating, film coating and/or various coatings aimed to modify release characteristics. The combined dosage forms preferred according to the present invention are obtained by combining independent unit dosage forms selected from the ones listed above that comprise dexlansoprazole and domperidone on pharmaceutically effective amounts preferably in a capsule.
The unit dosage forms can optionally be coated with protective coating, enteric coating, film coating, coloring coating and/or different coatings so as to provide various release characteristics. The unit dosage forms of dexlansoprazole according to the present invention can optionally be formulated to be delayed release while the unit dosage forms of domperidone can optionally be formulated to be constant release.
The unit dosage forms of present invention comprising domperidone on pharmaceutically acceptable amounts are preferably in granule, powder or pellet form while the unit dosage form comprising dexlansoprazole is preferably in micro tablet form.
The unit dosage forms of the present invention are formulated according to the characteristics of the active agent they comprise. Thus, pharmaceutically acceptable excipients comprised in separate dosage forms and their amounts can be identical or different. The pellet, granule or powder compositions of domperidone according to the present invention can comprise effective amounts of domperidone and one or more pharmaceutically acceptable excipients described in detail above.
The unit dosage forms comprising domperidone can be produced by any method in the prior art.
The method preferred to be used in production of powder compositions of domperidone of the present invention is preferably dry mixing wherein said method comprises mixing domperidone on a pharmaceutically effective amount, at least one pharmaceutically acceptable filling material, at least one lubricant and optionally at least another excipient. Domperidone pellets, which is another unit dosage form preferred according to the present invention, are preferably constant release pellets and preferably produced by the following method:
I. Domperidone and a pharmaceutically acceptable diluent or some part of the diluent mixture are mixed dry; the coloring agent and the filling material are added into the mixture and they are all mixed again,
II. Rest of the diluent in the first step is granulated with the granulation solution that is composed of at least one pharmaceutically acceptable binder and deionized water,
III. The dry active agent mixture obtained in the first step is added into the wet diluent granules obtained, they are mixed and pellets are prepared of this mixture,
IV. The pellets obtained are coated with the solution prepared by dissolving the rate controlling agent in a suitable solvent.
The micro tablets of dexlansoprazole preferred according to the present invention are composed of a tablet core comprising dexlansoprazole on an effective amount, at least one pharmaceutically acceptable disintegrants, at least one binder, at least one stabilizing agent, at least one rate controlling agent and optionally at least another excipient; a sub-coat on the core; an enteric coat on the sub-coat and optionally a coloring coat.
The stabilizing agents to be used in the micro tablet composition of dexlansoprazole and their amounts are selected such that pH of the composition is at a level to provide minimum degradation of dexlansoprazole. The amount preferred is in the range of 1% to 50%, preferably in the range of 1% to 40%, more preferably in the range of 1% to 30% with respect to weight of the core of the unit dosage form comprising dexlansoprazole. The stabilizing agent used in micro tablets of dexlansoprazole of the present invention can preferably be a magnesium salt, for instance magnesium oxide, magnesium carbonate, magnesium silicate and/or magnesium sulphate.
The production method for production of the micro tablets of domperidone of the present invention is preferably wet granulation and it comprises the following steps:
I. Preparing the granulation solution by mixing at least one pharmaceutically acceptable binder and one solvent or solvent mixture,
II. Mixing dexlansoprazole on an effective amount, at least one pharmaceutically acceptable disintegrant and optionally another excipient,
III. Granulating the mixture obtained in the second step with the granule solution obtained in the second step; drying and then sieving the granules,
IV. Mixing the obtained granules preferably with a cellulose derivative rate controlling agent and optionally another excipient; adding a pharmaceutically acceptable lubricant into the mixture, and mixing them together,
V. Compressing micro tablets of the final mixture,
VI. Coating the micro tablets obtained with a sub-coat, an enteric coat and finally a coloring coat layer.
A characteristic feature of the production method given above is that the pharmaceutically acceptable excipient in the second step of the method is a stabilizing agent.
A characteristic feature of the production method given above is that the mixing time of the lubricant given in the fourth step of the method is in the range of 1 to 20 minutes, preferably in the range of 1 to 10 minutes.
Another characteristic feature of the production method given above is that the compression force required for compressing micro tablets as given in the fifth step of the method is in the range of 10 to 300 kN, preferably in the range of 10 to 200 kN.
The obtained micro tablets comprising dexlansoprazole are mixed with unit dosage forms of the present invention comprising domperidone on pharmaceutically effective amounts and they are preferably filled into a capsule made of soft gelatin. The combination of the present invention and pharmaceutical compositions comprising said combination and the methods for their preparation can be explained with, but not limited to, the examples below.
Example 1. Film Coated Tablet Composition 25 mg dexlansoprazole and 5 mg domperidone are taken as active agents. The combination of dexlansoprazole and domperidone is granulated with pharmaceutically acceptable excipients. The granules are dried and then sieved under appropriate humidity and temperature conditions. Tablets are compressed from the obtained final product in an appropriate tablet compressing machine. Optionally, tablets can be film coated. Example 2. Combine Dosage Form-I
Diluent 45.00
Binder 0.80
Filling material 13.00
Rate controlling agent 1.00
Coloring agent 0.20
Total weight 100
The production method for enteric coated micro tablet composition comprising dexlansoprazole so as to be produced according to the formulation given above is as follows:
I. The mixture composed of dexlansoprazole, at least one disintegrant and magnesium oxide agent is granulated by a granulation solution obtained by mixing a pharmaceutically acceptable binder and solvent; the granules are dried and then sieved.
II. The rate controlling agent is added into the garnules obtained and the blend is mixed.
III. The lubricant is added into the mixture and the blend is mixed for 5 minutes.
IV. Micro tablets are compressed of the final mixture by imposing 1-300 kN of compression force.
V. The micro tablets are coated with subcoating first, then with enteric coating and lastly with coloring coating.
The method for production of constant release pellet composition comprising domperidone is as follows:
I. Domperidone and some part of the diluent or the diluent mixture are mixed dry; the coloring agent and the filling material are added into the mixture and the blend is mixed again.
II. Rest of the diluent in the first step is granulated with a granulation solution composed of the binder on the amount given above and deionized water.
III. The dry active agent mixture is added into the wet diluent granules obtained in the first step; they are mixed and pellets are obtained. IV. The pellets obtained are coated with a solution prepared by dissolving the rate controlling agent in a suitable solvent.
Dexlansoprale micro tablets and domperidone pellets produced according to the production methods and the formulation given above are combined preferably in a capsule made of soft gelatin.
Example 3. Combined Dosage Form-II
Other excipients 9.50
Total weight 100.00 Example 4. Combined Dosage From-III
Lubricant 0.50
Total weight 100.00
The micro tablet compositions of dexlansoprazole given in examples 3 and 4 are produced according to the production method given in example 2.
The powder compositions of domperidone given in said examples, on the other hand, prepared by dry mixing of domperidone and other excipients present in the formulations.
The micro tablets of dexlansoprazole and the powder compositions of domperidone obtained this way are combined in preferably a capsule made of soft gelatin.

Claims

1. A pharmaceutical composition characterized in that said composition comprises the active agents dexlansoprazole and domperidone.
2. The pharmaceutical composition according to claim 1 characterized in that the active agents are in separate dosage forms or in a single dosage form.
3. The pharmaceutical composition according to claim 2 characterized in that the components composing said composition are used simultaneously, sequentially or separately.
4. The pharmaceutical composition according to claims 1 to 3 characterized in that said composition comprises dexlansoprazole in the range of 5 mg to 180 mg and domperidone in the range of 0.25 mg to 100 mg.
5. The pharmaceutical composition according to claim 4 characterized in that said composition comprises dexlansoprazole in the range of 1 mg to 120 mg and domperidone in the range of 1 mg to 60 mg.
6. The pharmaceutical composition according to claim 5 characterized in that said composition comprises dexlansoprazole in the range of 15 mg to 60 mg and domperidone in the range of 5 mg to 15 mg.
7. The pharmaceutical composition according to claims 1 to 6 characterized in that said composition comprises pharmaceutically acceptable excipients selected from the group comprising pH adjusters, stabilizing agents, diluents, binders, coating materials designed to provide various release characteristics, disintegrants, anti-adhesive agents, plasticizers, rate controlling agents, filling materials, glidants, coloring agents, aqueous or non-aqueous solvents or combinations thereof.
8. The pharmaceutical composition according to claims 1 to 7 characterized in that said composition comprises the active agents in a single dosage form.
9. The pharmaceutical composition according to claim 8 characterized in that the active agents are formulated together and combined in a single dosage form.
10. The pharmaceutical composition according to claim 8 characterized in that the active agents are formulated as separate dosage forms and combined in a single dosage form.
11. The pharmaceutical composition according to claim 10 characterized in that the unit dosage forms are in micro tablet, coated tablet, effervescent tablet, soluble tablet, pellet, granule, powder form.
12. The pharmaceutical composition according to claim 11 characterized in that the unit dosage forms are coated with protective coating, enteric coating, coloring coating, film coating and/or coatings to provide various release characteristics.
13. The pharmaceutical composition according to claims 10 to 12 characterized in that the unit dosage forms are combined in a capsule made of soft gelatin.
14. The pharmaceutical composition according to claims 10 to 13 characterized in that the unit dosage form comprising dexlansoprazole is in micro tablet form.
15. The pharmaceutical composition according to claims 10 to 13 characterized in that the unit dosage form comprising domperidone is in pellet, granule or powder form.
EP11720903A 2010-04-26 2011-04-25 Pharmaceutical compositions inducing synergistic effect Withdrawn EP2563341A1 (en)

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US4066772A (en) 1975-07-21 1978-01-03 Janssen Pharmaceutica N.V. 1,3-Dihydro-1-[3-(1-piperidinyl)propyl]-2H-benzimidazol-2-ones and related compounds
SE9600072D0 (en) * 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients II
WO2004071374A2 (en) * 2003-02-11 2004-08-26 Torrent Pharmaceuticals Limited Once a day orally administered pharmaceutical compositions
BR0303794A (en) * 2003-09-05 2005-04-12 Medley S A Ind Farmaceutica Medication, Medication Kit, Medication Set, Medication Association and Medication Presenting Facilitated Presentation
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WO2006011159A2 (en) * 2004-06-21 2006-02-02 Torrent Pharmaceuticals Limited Stabilized pharmaceutical composition containing rabeprazole sodium with improved bioavailability
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