WO2012093972A1 - Water soluble dosage forms - Google Patents

Water soluble dosage forms Download PDF

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Publication number
WO2012093972A1
WO2012093972A1 PCT/TR2012/000003 TR2012000003W WO2012093972A1 WO 2012093972 A1 WO2012093972 A1 WO 2012093972A1 TR 2012000003 W TR2012000003 W TR 2012000003W WO 2012093972 A1 WO2012093972 A1 WO 2012093972A1
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WIPO (PCT)
Prior art keywords
range
water soluble
weight
formulations
acarbose
Prior art date
Application number
PCT/TR2012/000003
Other languages
French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Priority to EP12707405.2A priority Critical patent/EP2661252A1/en
Publication of WO2012093972A1 publication Critical patent/WO2012093972A1/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • 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

Definitions

  • the present invention relates to water soluble pharmaceutical compositions comprising acarbose and use of these compositions in diabetes, adiposity and hyperlipoidemia.
  • Diabetes is a chronic disease which is characterized by insufficient or lack of insulin production by the pancreas and leads to disorders of carbohydrate, lipid and protein metabolism. There are two major types of diabetes.
  • Type I diabetes grows because beta cells in the pancreas can produce very little or no insulin associated with autoimmune mechanisms. Insulin is a hormone which is responsible for reducing elevated blood sugar. Blood sugar level rises depending on reduction in amount or in efficiency of insulin (hyperglycemia). Type I diabetes generally develops in children or young adults. Type II diabetes is the most common type of diabetes and characterized by insulin resistance. In this type of diabetes, insulin is released properly but it cannot be sufficiently effective.
  • the primary treatment method for diabetic patients is diet and exercise. This treatment approach provides very little weight loss but regulates insulin sensitivity. Sometimes, it can be possible to control blood sugar level for a long period of time only with this treatment method. However, the tendency towards insulin resistance in these people never disappears; therefore, the diet, exercise and weight control should be maintained continuously. In the cases that diet and exercise are insufficient, the second step of the treatment is oral anti-diabetic drugs and insulin reinforcement.
  • the main oral anti-diabetics used in treatment of Type II diabetes are sulfonylureas, biguanides and alpha glucosidase inhibitors,
  • Acarbose which is an alpha glucosidase inhibitor was first disclosed in the patent document numbered DE2347782.
  • Acarbose is produced by fermentation of the microorganism called Actinoplanes utahensis.
  • Acarbose inhibits alpha glucosidase enzyme which is responsible for digestion of carbohydrates in lumen of the small intestine. Digestion and absorption of carbohydrates in the intestine are slowed down by inhibition of this enzyme; therefore elevation in blood sugar level after meals is prevented. Acarbose does not affect insulin release from the pancreas, insulin use in the tissues or glucose outflow from the liver. Therefore, acarbose does not cause hypoglycaemia when used singly.
  • acarbose can be preferred as a primary treatment in the case that there is diabetes that cannot be controlled by diet or it can be preferred as combination treatment option in the case that postprandial hyperglycemias cannot be prevented during the treatments of sulfonurea, biguanide or insulin.
  • the formulation comprising the active agent acarbose is marketed under the trade name Glucobay® in the form of 50 and 100 mg tablets.
  • solid dosage forms such as tablet cause difficulty of use generally in geriatric, pediatric and disabled patients who have swallowing difficulty. Feeling of obstruction and choking can o uf ⁇ rr3 ⁇ 4drviduals due to the ⁇ rob1 ⁇ 2n ⁇ e €umng- & pharyngeal and esophageal motility and consequently taking drug can be disgustful and painful for patients. In line with this, the patient delays drug intake and this situation decreases efficiency of the treatment significantly and affects life quality of the patient.
  • dosage forms which comprise the active agent acarbose and are easy-to-use for patients in order to be used in treatment of diabetes, adiposis and hyperlipidemia.
  • Suspension forms which are presented as an alternative in order to overcome the problems caused by solid dosage forms cannot be performed in most of the active agents due to the reasons that suspension forms have the possibility of causing high and/or uncontrolled dose intake and furthermore there is problems in physical and chemical stabilities of suspension forms after diluted; production costs of suspension forms are high and they pose problem in using and carrying.
  • acarbose is a hygroscopic molecule; therefore, it is quite hard to formulate acarbose in water soluble dosage forms such as suspension. Contact of the active agent with water leads to disintegration of the formulations in a shorter time than expected and quickly.
  • the present invention relates to water soluble dosage forms comprising the active agent acarbose; the methods for preparing these dosage forms and usage areas thereof.
  • Formulating the formulations of the present invention in water soluble dosage forms have enabled that required therapeutic benefit is provided by using less amount of active agent than the active agent amount comprised in the dosage forms in the prior art. Use of less active agent is also advantageous for the reason that it reduces side effect possibility that can be caused by the formulations.
  • one water soluble iOrmulations of the present invention is that the formulations comprise acarbose in the range of 1 % to 10 % by weight, preferably in the range of 1% to 9 % by weight, more preferably in the range of 1% to 8% by weight.
  • Another characteristic feature of the water soluble formulations of the present invention is that the formulations comprise acarbose in the range of 10-300 mg, preferably in the range of 20-200 mg, more preferably in the range of 50-150 mg.
  • one characteristic feature of the water soluble formulations of the present invention is that the formulations are formulated in the form of powder, granule, pellet, micro tablet or tablet.
  • the water soluble formulations of the present invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising effervescent couple, binder, lubricant, glidant, diluent, disintegrant, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent, humectant or combinations thereof in addition to the active agent.
  • a pharmaceutically acceptable excipient selected from a group comprising effervescent couple, binder, lubricant, glidant, diluent, disintegrant, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent, humectant or combinations thereof in addition to the active agent.
  • the binder that can be used in the water soluble formulations of the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol; water or the combinations thereof.
  • the binder used in the water soluble formulations of the present invention is selected from a group comprising lactose, sorbitol, polyethylene glycol or the combinations thereof.
  • the amount of the binder that can be used in the water soluble formulations of the present invention is in the range of 0% to 10% by weight, preferably in the range of 0.5% to 2% by weight.
  • the lubricant that can be used in the water soluble formulations of the present invention can be selected from sodium lauryl sulphate, calcium stearate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium chloride, carbowax 4000, talc or a combination thereof.
  • the amount of the lubricant used in the formulations of the present invention is in the range of 0% to 5% by weight, preferably in the range of 0.3% to 2% by weight; the lubricant which is particularly preferred is polyethylene glycol.
  • the glidant that can be used in the water soluble formulations of the present invention can be selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
  • the amount of the glidant used in the formulation of the present invention is in the range of 0% to 5% by weight.
  • the diluent that can be used in the water soluble formulations of the present invention can be selected from lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch, calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium carbonate, magnesium oxide or a combination thereof.
  • the inventors have unexpectedly found that the type and amount of the diluent used in the formulations prevent disintegration arising from hygroscopic characteristic of the active agent. According to this, stability of the formulations comprising small amount of the active agent acarbose could be preserved for a long period of time, for 24 months, with use of maltodextrin as diluent in the water soluble formulations of the present invention.
  • the amount of the diluent used in the water soluble formulations of the present invention is in the range of 1% to 10% by weight, preferably in the range of 2% to 7% by weight, more preferably in the range of 3% to 5% by weight.
  • one characteristic feature of the water soluble formulations of the present invention comprising acarbose is that the formulations comprise maltodextrin in the range of 1% to 10% by weight, preferably in the range of 2% to 7% by weight, more preferably in the range of 3% to 5% by weight.
  • the disintegrant that can be used in the water soluble formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose SOdium or micro crystalline cellulose; polyvinylpyrrolidone ; erospovidone;- aigini acid and its salts; chyles such as xanthan gum or veegum; ion-exchange resins or a combination thereof.
  • the amount of the disintegrant used in the formulation of the present invention is in the range of 0% to 70% by weight, preferably in the range of 0% to 50% by weight; and the disintegrant which is particularly preferred is starch or cellulose derivative.
  • the flavouring agent that can be used in the water soluble formulations of the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p- ment
  • the sweetener that can be used in the water soluble formulations of the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
  • the colouring agent that can be used in the water soluble formulations of the present invention can be selected from carotenoids and
  • the surfactant that can be used in the water soluble formulations of the present invention can be selected from sodium lauryl sulphate and magnesium lauryl sulphate or a combination thereof.
  • the antifoaming agent that can be used in the water soluble formulations of the present invention can be selected from simethicone emulsion and dimethyl siloxane, silicone oil or a combination thereof.
  • the viscosity agent that can be used in the water soluble formulations of the present invention can be selected from carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, colloidon, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof.
  • the stabilizing agent and/or agents that can be used in the water soluble formulations of the present invention can be selected from agents such as antioxidants, chelating agents, alkalinizing agents and photo-protectives.
  • the antioxidants can be selected from substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate or a combination thereof.
  • the chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or a combination thereof.
  • the alkalizing agents can be selected from alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, sodium aluminate; earth alkaline metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N-N'-dibenzylethylenediamine, diethanoleamine, ethylenediamine, meglumine, monosodium glutamate, polyacryline sodium, sodium alginate or a combination thereof.
  • alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphat
  • the photo-protective agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide or a combination thereof.
  • the humectant mentioned herein can be selected from anhydrous sodium sulphate, silica gel and potassium carbonate or a combination thereof.
  • the water soluble formulations of the present invention can be optionally prepared in effervescent or non-effervescent characteristic.
  • the formulations are prepared in effervescent form, the formulations also comprise a pharmaceutically acceptable effervescent couple in addition to the excipients specified above.
  • the acidic agent that can be used in the water soluble formulations of the present invention can be selected from a group comprising acedic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and/or hydrates, anhydrates or the combinations thereof.
  • the amount of the acidic agent that can be used in the water soluble formulations of the present invention is in the range of 0% to 85% by weight, preferably in the range of 0% to 75% by weight; and the acidic agent which is particularly preferred is citric acid and/or malic acid.
  • the basic agent that can be used in the water soluble formulations of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate and/or hydrates, anhydrates or the combinations thereof.
  • the amount of the basic agent that can be used in the water soluble formulations of the present invention is in the range of 0% to 40% by weight, preferably in the range of 0% to 30% by weight; and the basic agent which is particularly preferred is sodium carbonate or sodium hydrogen carbonate.
  • the water soluble formulations of the present invention basically comprise acarbose in the range of 1% to 10% by weight and the diluent in the range of 1% to 10% by weight.
  • the water soluble formulations of the present invention can optionally comprise the excipients given below in addition to the active agent and the diluent;
  • the water soluble formulations of the present invention can be produced by any one of the conventional production methods in the prior art such as wet granulation, dry granulation, dry blending.
  • the formulation of the present invention can be used in treatment of diabetes, adiposity and hyperlipidemia. All of the components used within the scope of the present invention are pharmaceutically suitable.
  • pharmaceutically suitable signifies that the component used is suitable for human use, has a few or no unexpected side effects (toxicity, irritations, allergic response) and provides a significant benefit to user.
  • the granulation solution is prepared by mixing the binder and the diluent. Acarbose and the effervescent couple are mixed in fluid bed and granulated with the granulation solution prepared. The granules obtained are mixed with the lubricant and the other excipients.
  • the formulation prepared can be packed in powder or granule form and also the formulation prepared can be compressed into tablets.
  • the components in the given amounts are packed after formed into powder or granule by any of the methods in the prior art.
  • the powder mixture which is sieved is filled into bottles or the components can be formed into dry powder by any of the methods in the prior art in order to be used in preparation of suspension.

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Abstract

The present invention relates to effervescent pharmaceutical formulations comprising acarbose and use of these compositions in diabetes, adiposity and hyperlipoidemia.

Description

WATER SOLUBLE DOSAGE FORMS
Technical Field
The present invention relates to water soluble pharmaceutical compositions comprising acarbose and use of these compositions in diabetes, adiposity and hyperlipoidemia. The Prior Art
Diabetes is a chronic disease which is characterized by insufficient or lack of insulin production by the pancreas and leads to disorders of carbohydrate, lipid and protein metabolism. There are two major types of diabetes.
Type I diabetes grows because beta cells in the pancreas can produce very little or no insulin associated with autoimmune mechanisms. Insulin is a hormone which is responsible for reducing elevated blood sugar. Blood sugar level rises depending on reduction in amount or in efficiency of insulin (hyperglycemia). Type I diabetes generally develops in children or young adults. Type II diabetes is the most common type of diabetes and characterized by insulin resistance. In this type of diabetes, insulin is released properly but it cannot be sufficiently effective.
In treatment of diabetes, it is aimed to reduce symptoms, improve life quality, prevent acute and chronic symptoms. The primary treatment method for diabetic patients is diet and exercise. This treatment approach provides very little weight loss but regulates insulin sensitivity. Sometimes, it can be possible to control blood sugar level for a long period of time only with this treatment method. However, the tendency towards insulin resistance in these people never disappears; therefore, the diet, exercise and weight control should be maintained continuously. In the cases that diet and exercise are insufficient, the second step of the treatment is oral anti-diabetic drugs and insulin reinforcement. The main oral anti-diabetics used in treatment of Type II diabetes are sulfonylureas, biguanides and alpha glucosidase inhibitors,
Acarbose which is an alpha glucosidase inhibitor was first disclosed in the patent document numbered DE2347782. Acarbose (formula I), chemical name of which is 0-{4- Amino-4,6-dideoxy-N-((lS,4R,5S-,6S)-4,5,6-trihydroxy-3-hydroxymethylcyclohex-2- enyl)-alpha-D-glucopyranosyl } -( 1 ->4)-0-alpha-D-glucopyranosyl-( 1 ->4)-D- glucopyranose, is an alpha glucosidase inhibitor. Acarbose is produced by fermentation of the microorganism called Actinoplanes utahensis.
Figure imgf000003_0001
(Formula 1) Acarbose inhibits alpha glucosidase enzyme which is responsible for digestion of carbohydrates in lumen of the small intestine. Digestion and absorption of carbohydrates in the intestine are slowed down by inhibition of this enzyme; therefore elevation in blood sugar level after meals is prevented. Acarbose does not affect insulin release from the pancreas, insulin use in the tissues or glucose outflow from the liver. Therefore, acarbose does not cause hypoglycaemia when used singly. Use of acarbose can be preferred as a primary treatment in the case that there is diabetes that cannot be controlled by diet or it can be preferred as combination treatment option in the case that postprandial hyperglycemias cannot be prevented during the treatments of sulfonurea, biguanide or insulin. Nowadays, the formulation comprising the active agent acarbose is marketed under the trade name Glucobay® in the form of 50 and 100 mg tablets.
However, solid dosage forms such as tablet cause difficulty of use generally in geriatric, pediatric and disabled patients who have swallowing difficulty. Feeling of obstruction and choking can o uf^rr¾drviduals due to the ^rob½n^^e€umng- & pharyngeal and esophageal motility and consequently taking drug can be disgustful and painful for patients. In line with this, the patient delays drug intake and this situation decreases efficiency of the treatment significantly and affects life quality of the patient. When the prior art is taken into consideration, there is need for development of dosage forms which comprise the active agent acarbose and are easy-to-use for patients in order to be used in treatment of diabetes, adiposis and hyperlipidemia.
Suspension forms which are presented as an alternative in order to overcome the problems caused by solid dosage forms cannot be performed in most of the active agents due to the reasons that suspension forms have the possibility of causing high and/or uncontrolled dose intake and furthermore there is problems in physical and chemical stabilities of suspension forms after diluted; production costs of suspension forms are high and they pose problem in using and carrying. In other aspect, acarbose is a hygroscopic molecule; therefore, it is quite hard to formulate acarbose in water soluble dosage forms such as suspension. Contact of the active agent with water leads to disintegration of the formulations in a shorter time than expected and quickly.
However, the inventors have achieved to prepare new and improved water soluble dosage forms that can be produced without being affected by hygroscopic characteristic of the active agent.
Detailed Description of the Invention
The present invention relates to water soluble dosage forms comprising the active agent acarbose; the methods for preparing these dosage forms and usage areas thereof. Formulating the formulations of the present invention in water soluble dosage forms have enabled that required therapeutic benefit is provided by using less amount of active agent than the active agent amount comprised in the dosage forms in the prior art. Use of less active agent is also advantageous for the reason that it reduces side effect possibility that can be caused by the formulations. According to this, one
Figure imgf000004_0001
water soluble iOrmulations of the present invention is that the formulations comprise acarbose in the range of 1 % to 10 % by weight, preferably in the range of 1% to 9 % by weight, more preferably in the range of 1% to 8% by weight. Another characteristic feature of the water soluble formulations of the present invention is that the formulations comprise acarbose in the range of 10-300 mg, preferably in the range of 20-200 mg, more preferably in the range of 50-150 mg.
According to this, one characteristic feature of the water soluble formulations of the present invention is that the formulations are formulated in the form of powder, granule, pellet, micro tablet or tablet.
The water soluble formulations of the present invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising effervescent couple, binder, lubricant, glidant, diluent, disintegrant, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent, humectant or combinations thereof in addition to the active agent.
The binder that can be used in the water soluble formulations of the present invention can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol; water or the combinations thereof. The binder used in the water soluble formulations of the present invention is selected from a group comprising lactose, sorbitol, polyethylene glycol or the combinations thereof.
In other aspect, the amount of the binder that can be used in the water soluble formulations of the present invention is in the range of 0% to 10% by weight, preferably in the range of 0.5% to 2% by weight. The lubricant that can be used in the water soluble formulations of the present invention can be selected from sodium lauryl sulphate, calcium stearate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium benzoate, sodium chloride, carbowax 4000, talc or a combination thereof. The amount of the lubricant used in the formulations of the present invention is in the range of 0% to 5% by weight, preferably in the range of 0.3% to 2% by weight; the lubricant which is particularly preferred is polyethylene glycol. The glidant that can be used in the water soluble formulations of the present invention can be selected from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof. The amount of the glidant used in the formulation of the present invention is in the range of 0% to 5% by weight.
The diluent that can be used in the water soluble formulations of the present invention can be selected from lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch, calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium carbonate, magnesium oxide or a combination thereof.
The inventors have unexpectedly found that the type and amount of the diluent used in the formulations prevent disintegration arising from hygroscopic characteristic of the active agent. According to this, stability of the formulations comprising small amount of the active agent acarbose could be preserved for a long period of time, for 24 months, with use of maltodextrin as diluent in the water soluble formulations of the present invention.
The amount of the diluent used in the water soluble formulations of the present invention is in the range of 1% to 10% by weight, preferably in the range of 2% to 7% by weight, more preferably in the range of 3% to 5% by weight.
In other words, one characteristic feature of the water soluble formulations of the present invention comprising acarbose is that the formulations comprise maltodextrin in the range of 1% to 10% by weight, preferably in the range of 2% to 7% by weight, more preferably in the range of 3% to 5% by weight.
The disintegrant that can be used in the water soluble formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose SOdium or micro crystalline cellulose; polyvinylpyrrolidone ; erospovidone;- aigini acid and its salts; chyles such as xanthan gum or veegum; ion-exchange resins or a combination thereof.
The amount of the disintegrant used in the formulation of the present invention is in the range of 0% to 70% by weight, preferably in the range of 0% to 50% by weight; and the disintegrant which is particularly preferred is starch or cellulose derivative. The flavouring agent that can be used in the water soluble formulations of the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p- menthane-3-carboxamide, 3,1-methoxy propane 1.2-diol or a combination thereof.
The sweetener that can be used in the water soluble formulations of the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof. The colouring agent that can be used in the water soluble formulations of the present invention can be selected from carotenoids and chlorophyll or a combination thereof.
The surfactant that can be used in the water soluble formulations of the present invention can be selected from sodium lauryl sulphate and magnesium lauryl sulphate or a combination thereof. The antifoaming agent that can be used in the water soluble formulations of the present invention can be selected from simethicone emulsion and dimethyl siloxane, silicone oil or a combination thereof.
The viscosity agent that can be used in the water soluble formulations of the present invention can be selected from carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, colloidon, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof.
The stabilizing agent and/or agents that can be used in the water soluble formulations of the present invention can be selected from agents such as antioxidants, chelating agents, alkalinizing agents and photo-protectives. The antioxidants can be selected from substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate or a combination thereof. The chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or a combination thereof.
The alkalizing agents can be selected from alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, sodium aluminate; earth alkaline metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate and organic compounds such as primary, secondary and tertiary amines, cyclic amines, N-N'-dibenzylethylenediamine, diethanoleamine, ethylenediamine, meglumine, monosodium glutamate, polyacryline sodium, sodium alginate or a combination thereof.
The photo-protective agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide or a combination thereof.
The humectant mentioned herein can be selected from anhydrous sodium sulphate, silica gel and potassium carbonate or a combination thereof.
The water soluble formulations of the present invention can be optionally prepared in effervescent or non-effervescent characteristic.
In the case that the formulations are prepared in effervescent form, the formulations also comprise a pharmaceutically acceptable effervescent couple in addition to the excipients specified above.
The term "effervescent couple" used here refers to use of an acidic agent and basic agent together.
The acidic agent that can be used in the water soluble formulations of the present invention can be selected from a group comprising acedic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and/or hydrates, anhydrates or the combinations thereof.
The amount of the acidic agent that can be used in the water soluble formulations of the present invention is in the range of 0% to 85% by weight, preferably in the range of 0% to 75% by weight; and the acidic agent which is particularly preferred is citric acid and/or malic acid.
The basic agent that can be used in the water soluble formulations of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate and/or hydrates, anhydrates or the combinations thereof.
The amount of the basic agent that can be used in the water soluble formulations of the present invention is in the range of 0% to 40% by weight, preferably in the range of 0% to 30% by weight; and the basic agent which is particularly preferred is sodium carbonate or sodium hydrogen carbonate. The water soluble formulations of the present invention basically comprise acarbose in the range of 1% to 10% by weight and the diluent in the range of 1% to 10% by weight.
The water soluble formulations of the present invention can optionally comprise the excipients given below in addition to the active agent and the diluent;
- the effervescent acid in the range of 0-85%
- the effervescent base in the range of 0-40%
- the binder in the range of 0- 10%
- the lubricant in the range of 0- 10%
- the glidant in the range of 0-5%
- the disintegrant in the range of 0-70%
- the other excipients in the range of 1-20%
The water soluble formulations of the present invention can be produced by any one of the conventional production methods in the prior art such as wet granulation, dry granulation, dry blending.
The formulation of the present invention can be used in treatment of diabetes, adiposity and hyperlipidemia. All of the components used within the scope of the present invention are pharmaceutically suitable. The term pharmaceutically suitable signifies that the component used is suitable for human use, has a few or no unexpected side effects (toxicity, irritations, allergic response) and provides a significant benefit to user.
The examples below are given in order to explain the invention. The scope of the invention is not limited to these examples and these examples are evaluated with the description above which is described in detail.
Example 1
Figure imgf000011_0001
The granulation solution is prepared by mixing the binder and the diluent. Acarbose and the effervescent couple are mixed in fluid bed and granulated with the granulation solution prepared. The granules obtained are mixed with the lubricant and the other excipients. The formulation prepared can be packed in powder or granule form and also the formulation prepared can be compressed into tablets.
Example 2
Figure imgf000012_0001
The components in the given amounts are packed after formed into powder or granule by any of the methods in the prior art.
Example 3
Figure imgf000013_0001
All of the components given are mixed and sieved. The powder mixture which is sieved is filled into bottles or the components can be formed into dry powder by any of the methods in the prior art in order to be used in preparation of suspension.

Claims

1. The formulations comprising acarbose characterized in that the formulations are formulated in water soluble form.
2. The water soluble formulations according to claim 1 characterized in that the formulations comprise acarbose in the range of 1 % to 10% by weight.
3. The water soluble formulations according to claims 1-2 characterized in that the formulations comprise acarbose in the range of 1 % to 9% by weight.
4. The water soluble formulations according to claims 1-3 characterized in that the formulations comprise acarbose in the range of 1% to 8% by weight.
5. The water soluble formulations according to any preceding claims characterized in that the formulations are formulated in powder, granule, pellet, micro tablet or tablet forms.
6. The water soluble formulations according to any preceding claims characterized in that the formulations comprise pharmaceutically suitable excipients in addition to the active agent acarbose.
7. The water soluble formulations according to claim 6 characterized in that the formulations comprise at least one pharmaceutically acceptable excipient selected from a group comprising effervescent couple, binder, lubricant, glidant, diluent, disintegrant, flavouring agent, sweetener, colouring agent, surfactant, antifoaming agent, viscosity agent, stabilizing agent, humectant or the combinations thereof in addition to the active agent.
8. The water soluble formulations according to claim 7 characterized in that the diluent comprised in the formulations is selected from a group comprising lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch, calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium carbonate, magnesium oxide or a combination thereof.
9. The water soluble formulations according to claim 8- characterized in that the diluent comprised in the formulations is maltodextrin.
10. The water soluble formulations according to claim 9 characterized in that the amount of the diluent is in the range of 1% to 10% by weight.
11. The water soluble formulations according to claims 9-10 characterized in that the amount of the diluent is in the range of 2% to 7% by weight.
12. The water soluble formulations according to claims 9-11 characterized in that the amount of the diluent is in the range of 3% to 5% by weight.
13. The water soluble formulations according to any preceding claims characterized in that the formulations comprise
- acarbose in the range of 1% to 10% by weight
- the effervescent acid in the range of 0-85% by weight
- the effervescent base in the range of 0-40% by weight
- the binder in the range of 0- 10% by weight
- the lubricant in the range of 0- 10% by weight
- the glidant in the range of 0-5% by weight
- the diluent in the range of 1 - 10% by weight
- the disintegrant in the range of 0-70% by weight and
- optionally the other excipients in the range of 1-20% by weight.
PCT/TR2012/000003 2011-01-06 2012-01-06 Water soluble dosage forms WO2012093972A1 (en)

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WO2013115742A1 (en) * 2012-01-31 2013-08-08 Mahmut Bilgic Pharmaceutical composition comprising alpha-glucosidase inhibitor
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