WO2016114734A1 - Pharmaceutical formulation of trimebutine maleate and simethicone comprising acidifying agent - Google Patents
Pharmaceutical formulation of trimebutine maleate and simethicone comprising acidifying agent Download PDFInfo
- Publication number
- WO2016114734A1 WO2016114734A1 PCT/TR2016/000004 TR2016000004W WO2016114734A1 WO 2016114734 A1 WO2016114734 A1 WO 2016114734A1 TR 2016000004 W TR2016000004 W TR 2016000004W WO 2016114734 A1 WO2016114734 A1 WO 2016114734A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- simethicone
- composition according
- acidifying agent
- pharmaceutical composition
- tablet
- Prior art date
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Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
Definitions
- the invention relates to using anhdyrous dibasic calcium phosphate and acidifying agent in pharmaceutical dosage forms of trimebutine maleate and simethicone.
- Trimebutine maleate is a gastrointestinal motility regulator agent and used for functional intestinal disorders. This regulator activity is observed in all gastrointestinal tract. It regulates physiological motility in functional gastrointestinal diseases related to motility disorder. It is used for the treatment of irritable bowel syndorme, functional gastrointestinal disorders and gastrointestinal polymorph symptoms.
- Simethicone is an activated dimethicone and it acts as antifoam agent. Simethicone dispers and prevents the formation of mucous surrounded gas pockets in the gastrointestinal tract thereby reducing flatulance. Simethicone is an antiflatulent defoaming agent used for the relief of gastrointestinal gas pain.
- trimebutine maleate and simethicone have different physicochemical properties, they are difficult to formulate together when stability, bioavailability of the product and manufacturing difficulty is considered.
- simethicone and trimebutine maleate are in the same phramaceutical formulation simethicone inhibits solubility of trimebutine maleate, only a small amount of trimebutine maleate solved and more over during expiry period solubility decreased.
- Manufacturing a homogeneous, high quality pharmaceutical combination product of trimebutin maleate and simethicone with acceptable disintegration time and dissolution profile is only possible by admixing simethicone with suitable form of anhydrous dibasic calcim phosphate and using acidifying agent.
- EP0891776 discloses the simethicone solid oral dosage forms where dibasic calcium phosphate is used. In order to prepare solid dosage form having good flowability anhydrous dibasic calcium phosphate 30-90% and simethicon 10-30% was used. But the unit formula does not include trimebutine.
- Trimebutine and simethicone combination product described in US2008038336 application combines trimebutine maleate with simethicone by using 30% powder simethicone.
- Present invention provides a homogenous trimebutine maleate and simethicone combination product with high quality, good disintegration and good dissolution.
- a pharmaceutical composition of trimebutine maleate and simethicone which is stabil, pharmacologically equivalent to pharmaceutical products comprising trimebutine or simethicone as single which can be manufactured reproducible and where necessary amounts of active ingredients released can also be provided by the present invention.
- Another aspect of this invention is dissolution profile enhanced pharmaceutical composition of trimebutine maleate and simethicone comprising acidifying agent and suitable form of dibasic calcium phosphate where simethicone is adsorbed.
- trimebutine maleate and simethicone active ingredients are formulated with anhydrous dibasic calcium phosphate and acidifying agent.
- adsorbents auxilary adsorbents
- anhydrous dibasic clacium phosphate can be used together with anhydrous dibasic clacium phosphate.
- Anhydrous dibasic calcium phosphate used in this invention has specific surface area which is over 2 m 2 /g and oil adsorbtion capacity which is over 0.4 ml/g.
- adsorbents auxilary adsorbent
- dibasic calcium phosphate can be used together with dibasic calcium phosphate.
- the subject of this invention can be used in pharmaceutical dosage forms such as tablet, monolithic tablet, bilayer tablet, capsule, chewable tablet, efervescent tablet but not limited to these.
- triembutine maleate in the unit formula is prefered to be between 100-300 mg.
- Daily maximum dose is 600 mg/day.
- Dose can be calculated according to age and weight.
- simethicone in the unit formula is prefered to be between 20-125 mg.
- Daily maximum dose is 500 mg/day. Dose can be calculated according to age and weight.
- trimebutine and simethicone respectively in the doses 100 mg/60 mg, 100 mg/80 mg, 100 mg/125 mg, 200 mg/60 mg, 200 mg/80 mg, 200 mg/125 mg, 200 mg/200 mg, 200 mg/300 mg.
- the granules for each of trimebutine and simethicone prepared seperately in the present invention.
- Pharmaceutically acceptable disintegrant, binder, diluent, lubricant, glidant can be use during preparation of granules.
- lactose monohydrate sugar, sucrose, sorbitol, xylitol, dextrose, lactose, fructose, mannitol, aspartame, saccharin sodium, starch; as disintegrant sodium starch glycolate, agar, calcium carbonate, starch, methyl cellulose, sodium alginate; as binder gelatine, povidone, cellulose derivatives, carbohydrate derivatives, sugar alcohols, starch, paraffin, polyethylene glycol; as glidant and/or lubricant magnesium stearate, stearic acid, sodium stearyl fumarate, tribasic calcium, colloidal silicon dioxide, magnesium silicate, talc, calcium stearate, sodium acetate, sodium benzoate, glycol, polyethylene glycol, silica, cellulose derivatives, oils; as surfactants polysorbate 80, poloxamer or sodium lauryl sulfate can be used.
- This invention is not limited to
- Liquid form of simethicone must be adsorbed to powdered excipients.
- anhydrous dibasic calcium phosphate is used for this aim. Spesific surface area and oil adsorbtion capacity of anhydrous dibasic calcium phosphate is important parameters.
- solubility of trimebutine maleate is provided by using anhydrous dibasic calcium phosphate with spesific surface area over 2 m /g and with oil adsorbtion capacity over 0.4 ml/g.
- Anhydrous dibasic calcium phosphate which has physicochemical properties as described above is at least 3 times of simethicone by weight.
- Acidifying agent can be pharmaceutically acceptable weak acid such as tartaric acid, citric acid but not limited to these two. In this invention it is prefered to use citric acid as acidifying agent.
- adsorbents can be used together with anhydrous dibasic calcium phsophate.
- adsorbents can be at least one of talc, colloidal silicon dioxide, celulose derivatives, starch or or their mixture but not limited to these.
- colloidal silicon dioxide is preferably used as auxiliary adsorbent.
- Subject of this invention can be applied to monolithic tablet, bilayer tablet, capsule, chewing tablet, effervescent tablet pharmaceutical dosage forms of trimebutine maleate and simethicone combination.
- bilayer tablet formulation can be manufactured according to known technolgy and methods deciibed in the description and it is brought to use in desired pharmaceutical dosage form.
- bilayer tablet formulation can be manufactured according to known technology methods decribed in the description and it is brought to use in desired pharmaceutical dosage form.
Abstract
This invention is about a pharmaceutical product comprising trimebutine maleate and simethicone.
Description
DESCRIPTION
Pharmaceutical Formulation of Trimebutine Maleate and Simethicone
Comprising Acidifying Agent
Technical Field
The invention relates to using anhdyrous dibasic calcium phosphate and acidifying agent in pharmaceutical dosage forms of trimebutine maleate and simethicone.
Previous Technique
Trimebutine maleate is a gastrointestinal motility regulator agent and used for functional intestinal disorders. This regulator activity is observed in all gastrointestinal tract. It regulates physiological motility in functional gastrointestinal diseases related to motility disorder. It is used for the treatment of irritable bowel syndorme, functional gastrointestinal disorders and gastrointestinal polymorph symptoms.
Simethicone is an activated dimethicone and it acts as antifoam agent. Simethicone dispers and prevents the formation of mucous surrounded gas pockets in the gastrointestinal tract thereby reducing flatulance. Simethicone is an antiflatulent defoaming agent used for the relief of gastrointestinal gas pain.
Gas, pain, flatulence symptoms occur during gastrointestinal motility disturbance. For this reason it is important to use a pharmaceutical agent preventing symptoms occured in gastroinetstinal motility disturbance together with gastrointestinal motility regulators in order to increase treatment success and patient pleasure. Therefore use of trimebutine and simethicone together will be ideal canditate for the relief of functional intestinal disorders.
The liquid form of simethicone must be adsorbed to an adsorbent in order to prepare solid oral dosage forms of simethicone.
Since trimebutine maleate and simethicone have different physicochemical properties, they are difficult to formulate together when stability, bioavailability of the product and manufacturing difficulty is considered.
Applicants find out that when simethicone and trimebutine maleate are in the same phramaceutical formulation simethicone inhibits solubility of trimebutine maleate, only a small amount of trimebutine maleate solved and more over during expiry period solubility decreased. Manufacturing a homogeneous, high quality pharmaceutical combination product of trimebutin maleate and simethicone with acceptable disintegration time and dissolution profile is only possible by admixing simethicone with suitable form of anhydrous dibasic calcim phosphate and using acidifying agent.
EP0891776 discloses the simethicone solid oral dosage forms where dibasic calcium phosphate is used. In order to prepare solid dosage form having good flowability anhydrous dibasic calcium phosphate 30-90% and simethicon 10-30% was used. But the unit formula does not include trimebutine.
Combination products of trimebutine maleate and simethicone was first of all described in US2008038336 application. Trimebutine and simethicone combination product described in US2008038336 application, combines trimebutine maleate with simethicone by using 30% powder simethicone.
There is a need to develop stabil, pharmacologically active pharmaceutical product with reproducible, reliable manufacturing method comprising trimebutine maleate and simethicone together.
Brief Description of Invention
Present invention provides a homogenous trimebutine maleate and simethicone combination product with high quality, good disintegration and good dissolution.
A pharmaceutical composition of trimebutine maleate and simethicone which is stabil, pharmacologically equivalent to pharmaceutical products comprising trimebutine or simethicone as single which can be manufactured reproducible and where necessary amounts of active ingredients released can also be provided by the present invention.
Another aspect of this invention is dissolution profile enhanced pharmaceutical composition of trimebutine maleate and simethicone comprising acidifying agent and suitable form of dibasic calcium phosphate where simethicone is adsorbed.
Detail Description of Invention
In this invention trimebutine maleate and simethicone active ingredients are formulated with anhydrous dibasic calcium phosphate and acidifying agent.
In this invention other adsorbents (auxilary adsorbents) can be used together with anhydrous dibasic clacium phosphate.
Anhydrous dibasic calcium phosphate used in this invention has specific surface area which is over 2 m2/g and oil adsorbtion capacity which is over 0.4 ml/g.
In this invention other adsorbents (auxilary adsorbent) can be used together with dibasic calcium phosphate. The subject of this invention can be used in pharmaceutical dosage forms such as tablet, monolithic tablet, bilayer tablet, capsule, chewable tablet, efervescent tablet but not limited to these.
In this invention triembutine maleate in the unit formula is prefered to be between 100-300 mg. Daily maximum dose is 600 mg/day. Dose can be calculated according to age and weight. In this invention simethicone in the unit formula is prefered to be between 20-125 mg. Daily maximum dose is 500 mg/day. Dose can be calculated according to age and weight.
In this invention it has been prefered to combine trimebutine and simethicone respectively in the doses 100 mg/60 mg, 100 mg/80 mg, 100 mg/125 mg, 200 mg/60 mg, 200 mg/80 mg, 200 mg/125 mg, 200 mg/200 mg, 200 mg/300 mg.
The granules for each of trimebutine and simethicone prepared seperately in the present invention. Pharmaceutically acceptable disintegrant, binder, diluent, lubricant, glidant can be use during preparation of granules. As filler celulose derivatives, lactose monohydrate, sugar, sucrose, sorbitol, xylitol, dextrose, lactose, fructose, mannitol, aspartame, saccharin sodium, starch; as disintegrant sodium starch glycolate, agar, calcium carbonate, starch, methyl cellulose, sodium alginate; as binder gelatine, povidone, cellulose derivatives, carbohydrate derivatives, sugar alcohols, starch, paraffin, polyethylene glycol; as glidant and/or lubricant magnesium stearate, stearic acid, sodium stearyl fumarate, tribasic calcium, colloidal silicon dioxide, magnesium silicate, talc, calcium stearate, sodium acetate, sodium benzoate, glycol, polyethylene glycol, silica, cellulose derivatives, oils; as surfactants polysorbate 80, poloxamer or sodium lauryl sulfate can be used. This invention is not limited to excipients described here.
Liquid form of simethicone must be adsorbed to powdered excipients. In this invention anhydrous dibasic calcium phosphate is used for this aim. Spesific surface area and oil adsorbtion capacity of anhydrous dibasic calcium phosphate is important parameters. In the combination product solubility of trimebutine maleate is provided by using anhydrous dibasic calcium phosphate with spesific surface area over 2 m /g and with oil adsorbtion capacity over 0.4 ml/g.
Anhydrous dibasic calcium phosphate which has physicochemical properties as described above is at least 3 times of simethicone by weight.
In this invention in addition to adsorbtion of simethicone to anhydrous dibasic calcium phosphate final tablet pH should be within 4-5 in order to enhance the solubility of trimebutine. For this reason at least one acidifying agent is used in the unit formula.
Acidifying agent can be pharmaceutically acceptable weak acid such as tartaric acid, citric acid but not limited to these two. In this invention it is prefered to use citric acid as acidifying agent.
In this invention other adsorbents (auxiliary adsorbents) can be used together with anhydrous dibasic calcium phsophate. These adsorbents can be at least one of talc, colloidal silicon dioxide, celulose derivatives, starch or or their mixture but not limited to these. In this invention, colloidal silicon dioxide is preferably used as auxiliary adsorbent.
Subject of this invention can be applied to monolithic tablet, bilayer tablet, capsule, chewing tablet, effervescent tablet pharmaceutical dosage forms of trimebutine maleate and simethicone combination.
Below examples are to describe the invention however does not limit the scope of the invention.
Examples
Example 1: Bilayer Tablet Formulation
Above described bilayer tablet formulation can be manufactured according to known technolgy and methods deciibed in the description and it is brought to use in desired pharmaceutical dosage form.
Example 2: Monolithic Tablet Formulation
Magnesium stearate 2
Above described bilayer tablet formulation can be manufactured according to known technology methods decribed in the description and it is brought to use in desired pharmaceutical dosage form.
According to common concepts described within the application many applications may be developed with the subject of the invention "Pharmaceutical Formulation of Trimebutine Maleate and Simethicone Comprising Acidifying Agent". Invention is not limited to examples described within the application but mainly according to claims.
Claims
1. A pharmaceutical composition of trimebutine maleate, simethicone, comprising anhydrous dibasic calcium phosphate and acidifying agent.
2. A pharmaceutical composition according to claim 1 where weak acids used as acidifying agent.
3. A pharmaceutical composition according to claim 2 where citric acid is used as acidifying agent.
4. A composition according to claiml where additional adsorbent is used together with anhydrous dibasic calcium phosphate.
5. A composition according to claim 4 where additional adsorbent is talc, colloidal silicon dioxide, starch and/or cellulose derivatives.
6. A pharmaceutical composition according to claim 5 where colloidal silicon dioxide is used as additional adsorbent.
7. A pharmaceutical composition according to claim 1 comprising disintegrant, diluent, binder, glidant, lubricant, surfactant as excipient.
8. Pharmaceutical composition according to claim 7 where pharmaceutical dosage form is monolithic tablet, bilayer tablet, capsule, chewing tablet, efervescan tablet.
Use of a composition according to any of above claims for the manufacture of a medicament to treat gastrointestinal disorders
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201500551 | 2015-01-16 | ||
| TR2015/00551 | 2015-01-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016114734A1 true WO2016114734A1 (en) | 2016-07-21 |
Family
ID=55485263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2016/000004 WO2016114734A1 (en) | 2015-01-16 | 2016-01-11 | Pharmaceutical formulation of trimebutine maleate and simethicone comprising acidifying agent |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2016114734A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108159003A (en) * | 2018-01-22 | 2018-06-15 | 山西振东安特生物制药有限公司 | A kind of Trimebutine Maleate soluble particles preparation and preparation method thereof |
| CN113171353A (en) * | 2021-04-25 | 2021-07-27 | 海南普利制药股份有限公司 | Trimebutine maleate tablet |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03275622A (en) * | 1990-03-26 | 1991-12-06 | Teisan Seiyaku Kk | Oral solid preparation containing trimebutine maleate |
| EP0891776A1 (en) | 1997-07-17 | 1999-01-20 | McNEIL-PPC, INC. | Simethicone/anhydrous calcium phosphate compositions |
| US20080038336A1 (en) | 2006-08-10 | 2008-02-14 | Marta Luz Torres Esquea | Solid pharmaceutical composition containing a combination of an intestinal motility regulating agent and an antiflatulent |
| EP2641598A2 (en) * | 2010-11-16 | 2013-09-25 | Posi Visionary Solutions LLP | Orally administered pharmaceutical composition for the treatment of irritable bowel syndrome, comprising an intestinal motility modifier, an agent that prevents gas retention, and digestive enzymes, and preparation method thereof |
-
2016
- 2016-01-11 WO PCT/TR2016/000004 patent/WO2016114734A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03275622A (en) * | 1990-03-26 | 1991-12-06 | Teisan Seiyaku Kk | Oral solid preparation containing trimebutine maleate |
| EP0891776A1 (en) | 1997-07-17 | 1999-01-20 | McNEIL-PPC, INC. | Simethicone/anhydrous calcium phosphate compositions |
| US20080038336A1 (en) | 2006-08-10 | 2008-02-14 | Marta Luz Torres Esquea | Solid pharmaceutical composition containing a combination of an intestinal motility regulating agent and an antiflatulent |
| EP2641598A2 (en) * | 2010-11-16 | 2013-09-25 | Posi Visionary Solutions LLP | Orally administered pharmaceutical composition for the treatment of irritable bowel syndrome, comprising an intestinal motility modifier, an agent that prevents gas retention, and digestive enzymes, and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| BALIARDA: "Eumotil S", 1 April 2010 (2010-04-01), XP002756718, Retrieved from the Internet <URL:http://www.baliarda.com.ar/esp/PDF/Eumotil%20S.pdf> [retrieved on 20160419] * |
| DATABASE WPI Week 199204, Derwent World Patents Index; AN 1992-028855, XP002756719 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108159003A (en) * | 2018-01-22 | 2018-06-15 | 山西振东安特生物制药有限公司 | A kind of Trimebutine Maleate soluble particles preparation and preparation method thereof |
| CN113171353A (en) * | 2021-04-25 | 2021-07-27 | 海南普利制药股份有限公司 | Trimebutine maleate tablet |
| CN113171353B (en) * | 2021-04-25 | 2022-10-21 | 海南普利制药股份有限公司 | Trimebutine maleate tablet |
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