WO2014081338A1

WO2014081338A1 - Medicinal agent in the form of an orodispersible tablet and method for producing same

Info

Publication number: WO2014081338A1
Application number: PCT/RU2013/000929
Authority: WO
Inventors: Максим Эдуардович ЗАПОЛЬСКИЙ; Аллан Герович БЕНИАШВИЛИ; Маргарита Алексеевна МОРОЗОВА
Original assignee: Zapolsky Maxim Eduardovich
Priority date: 2012-11-20
Filing date: 2013-10-21
Publication date: 2014-05-30
Also published as: RU2503447C1

Abstract

The invention relates to the field of pharmaceutics and medicine, and more particularly to agents used in the case of various spastic states of the gastrointestinal tract and the pancreaticobiliary system, particularly in the case of irritable bowel syndrome (IBS), and to methods for producing said agents. The medicinal agent in the form of an orodispersible tablet is characterized in that it contains a combination of hyoscine butylbromide and diclofenac or the sodium salt thereof together with polacrilin potassium, where the ratio of diclofenac or the sodium salt thereof to polacrilin potassium is 1:2, and pharmaceutically acceptable additives, including mannitol, aspartame, crospovidone, polyvinylpyrrolidone K30, a flavouring agent and anhydrous colloidal silicon dioxide. The tablets exhibit improved bioavailability of the active ingredient.

Description

Drug in the form

orodispersed tablet and method for producing a medicinal product

The invention relates to the field of pharmaceuticals and medicine, in particular to agents used in various spastic conditions of the gastrointestinal tract and pancreaticobiliary system, especially with irritable bowel syndrome (IBS) and methods for their preparation.

State of the art

Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain, discomfort, bloating and impaired bowel behavior in the absence of any organic causes.

The prevalence of IBS among the population is 14–48%. In women, this pathology is observed 2-4 times more often than in men. According to some reports, for example, in the United States, the cost of treating this disease annually is $ 2 billion. Patients with IBS have a significantly reduced ability to work, sleep, sexual activity, and other disorders that interfere with normal life. Still true causes of IBS have not been established. IBS is believed to result from motor and sensory disturbances in the intestine. An important role in this is played by disorders of the normal function of the central nervous system (CNS). Patients have abnormal intestinal motility, impaired secretion in the intestines, and changes in visceral sensitivity. With IBS, both the small and large intestines exhibit increased reactivity in the form of intestinal cramping, slowing down or accelerating the motility of various irritants, including drugs and even food. Patients are prone to depression, anxiety, carcinophobia, they often respond more actively to stress. Borderline neuropsychiatric disorders are found in 75% of patients with IBS. Thus, the leading factors in the pathogenesis of IBS are given to the following factors: psychological, impaired motility and visceral sensitivity, changes in the chemical composition of intestinal contents.

There is a large selection of drugs of various pharmacological groups that can be used for IBS, in particular this:

- MH - anticholinergics - hyoscine butyl bromide;

- antagonists of cholecystokinin - loxiglumide; - somatostatin analogues;

- 5-hydroxytryptamine 3 antagonists (5NTZ) - ondansetron;

- myotropic antispasmodics (mebeverine hydrochloride, otilonium bromide and pinoverium bromide)

- regulators of intestinal motility (trimebutin), etc.

Hyoscine butyl bromide was created in Germany in 1951. It is highly selective for Ml and MH subtypes of receptors, which are most found in the upper gastrointestinal tract, gall bladder, and biliary ducts, which determines its frequent use in this pathology.

At the same time, it has a low systemic bioavailability, which leads to variability of the manifestations of the action upon enteral administration.

Thus, the effectiveness of treatment with its help of well-known tablets is often assessed as insufficient.

In addition, conventional tablets for oral administration are not always convenient for patients - they require drinking water, chewing tablets affect the teeth. Many people experience complications due to the need to swallow regular tablets, which are often quite large. Problems with not taking pills (difficulty breathing, choking caused by clogging throat), often lead to non-compliance with the dosage and even to refusal to take medication. These problems affect, in particular, children, the elderly, patients suffering from disorders of swallowing reflexes or pathologies that violate salivation.

For such groups of patients, rapidly dispersible forms are developed in the mouth.

RF patent 2424793 relates to a pharmaceutical composition in the form of a food film for oral administration, where the food film includes diclofenac in the form of free acid or diclofenac resinate in an amount of from 10 to 50 wt.% And a film-forming polymer in an amount of from 10 to 80 wt.% In the calculation on the dry weight of the resulting food film. The composition contains from 10 to 50 mg of diclofenac in a dissolved or uniformly dispersed state, while the food film has a thickness of 20-250 microns. The invention provides for the rapid decomposition of food film in the patient's oral cavity in less than 20 seconds.

Patent RU 2242968 C2 is known, which relates to a fast-dispersing solid dosage form which dissolves in the oral cavity within sixty (60), more preferably thirty (30), most preferably ten (10) seconds. As a matrix modified starch is used, and hyoscine butyl bromide may be selected as the active substance.

Another new direction in the development of fast dispersible tablets are orodispersible tablets.

Due to the rapid destruction that becomes possible in the presence of saliva, the orodispersible tablet disintegrates into easily swallowed small particles within a few tens of seconds after ingestion. In the case of a form with instant release of the active substance, oral dispersion provides faster absorption by the body compared with swallowed forms due to the increase in the area of exchange with physiological fluids.

For example, the patent of the Russian Federation 2317812 is known, which discloses an orodisperse solid dosage form containing homogeneous granules of lactose and starch obtained by drying by co-spraying. A variety of pharmacologically active substances can be included as an active principle. However, these excipients may have a negative effect when used with irritable bowel syndrome.

As the closest analogue, Levsin sublingual tablets containing as of the active principle, belladonna alkaloids, and as auxiliary substances, lactose, magnesium stearate, stearic acid, mannitol, starch and dye, which can be used in various spastic conditions, including irritable bowel syndrome. and method for their preparation

(http://www.medapharma.us/products/pi/LevsinSLTablets_PI.pdf).

Disclosure of invention

The objective of the present invention is to develop a composition and method of an effective dosage form that can be used in various spastic conditions of the gastrointestinal tract and pancreatic-biliary system, especially with irritable bowel syndrome (IBS).

The problem is solved by a new drug in the form of an orodispersed tablet containing a combination of hyoscine butyl bromide and diclofenac or its sodium salt in combination with an ion-exchange resin (1: 2), as well as a method for producing this drug, characterized in that mannitol and silicon dioxide are mixed anhydrous, 20% solution of polyvinylpyrrolidone K 30, granulate the mixture by spraying in a fluidized bed, separately mix previously the resulting complex of Diclofenac or diclofenac sodium with potassium polacryllin, hyoscine butyl bromide, Crospovidone, aspartame and flavoring, combine the resulting mixtures and mix until a homogeneous state is obtained, followed by tablet compression method, including preliminary compression with a force of 2-3 kN and final compression with force 8-10 kN.

The proposed tool has the following composition, wt.%:

Hyoscine butyl bromide 3.7-4.3

Diclofenac complex or

diclofenac sodium with potassium

half-acrylic 58.0-63.0

Mannitol 13.11-14.49

Aspartame 9.0-10.5

Crospovidone 6.08-6.72

Polyvinylpyrrolidone K 30 1.9-2.1

Flavoring additive 2.83-3.57

Silicon Colloidal Dioxide

anhydrous 0.38-0.42

Orodispersed tablets are white, round, uncovered, flat tablets with a beveled edge.

Preferred dosages of the active principle are per tablet: Hyoscine butyl bromide 1-50.0 mg

Diclofenac 2-200 mg

Potassium Polacrillin (PP) is a monofunctional minimally cross-linked carboxylic acid exchange resin obtained by co-polymerization of methacrylic acid with divinylbenzene and subsequently neutralized with potassium hydroxide:

PP is an effective disintegrating agent in a low concentration in various formulations in the form of tablets, including many hydrophobic formulations, where standard disintegrating agents are not very effective.

In the claimed composition, it is used to obtain a complex with diclofenac or its diclofenac sodium salt resinate.

Mannitol has an additional stabilizing effect on the composition. Aspartame sugar substitute is used in this form as a digestible low-calorie sweetener, providing, in combination with other components, acceptable palatability.

In the proposed composition, the optimal combination of two types of polyvinylpyrrolidone - Crospovidone and Polyvinylpyrrolidone K 30 was also selected. This combination provides the required compressibility, stability, and also affects the taste of the tablets.

As a flavoring additive, you can enter food acceptable additives, such as lemon, tangerine, blueberry, peppermint, etc., preferably dry mint.

Anhydrous colloidal silicon dioxide was introduced into the composition as an antifriction and dispersing component, for example, Aerosil 200 brand dioxide can be used.

Effect: increase bioavailability and, accordingly, a decrease in the variability of action.

A method of producing tablets is as follows: Mannitol, silicon dioxide, colloidal anhydrous, 20% solution of polyvinylpyrrolidone K 30 are mixed, the mixture is granulated by spraying in a fluidized bed. Separately mix the pre-obtained complex of Diclofenac or diclofenac sodium with potassium polacrilin (Diclofenac resinate or diclofenac resinate) taken at a ratio of 1: 2, with hyoscine butyl bromide, crospovidone, aspartame and flavoring.

Combine the resulting mixture and mix until a homogeneous state is obtained. The mixture is tabletted by the compression method in two stages: preliminary compression with a force of 2-3 kN and final compression with a force of 8-10 kN. The hardness of the tablets is 25-44 N.

The best example of carrying out the invention

Examples of carrying out the invention.

Example 1

Hyoscine butyl bromide 3.7

Diclofenac complex or

diclofenac sodium with potassium

polacriline 63.0

Mannitol 13.11

Aspartame 9.0

Crospovidone 6.08

Polyvinylpyrrolide! 1.9

Flavoring Additive 2.83

Aerosil 200 0.38

Stage A: Granulation Weighing and sieving fillers for the granulation process:

Mannitolum (13.11 kg)

Aerosil 200 (0.38 kg)

Polyvinylpyrrolidone K 30 (PVP K 30) (1.9 kg)

All suspended material is sieved through a 40 mesh strainer. The fluidized bed granulator is preheated before filling the mixture and before spraying the solution of the sprayed material to begin to flow the mixture of Mannitol and Aerosil 200 for at least 3 minutes.

Obtaining a 20% solution of PVP K 30 using purified distilled water according to the European Pharmacopoeia standard.

Spraying a solution of spray material into a fluidized bed granulator tank. The moisture content in the granulate is between 1.0 and 3.0%.

Stage B: obtaining the Complex Diclofenac Sodium Resinate

Sodium Diclofenac (21.0 kg) and Potassium Polacrillin (42.0 kg) are weighed and sieved. Sifted Potassium Polacrillin is slowly added to warm purified distilled water (temperature from 35 ° C to 40 ° C). the above distilled water with stirring and stirring is continued for 2 hours. Slowly add Diclofenac Sodium to the above resin solution with stirring. The pH of the solution of Diclofenac Sodium - Resin should be 5-6.

Stirred for 2 hours at a temperature between 35 ° C and

40 ° C.

Leave the mixture overnight. The Diclofenac Sodium - Resin complex will be stabilized, and a pop-up liquid will be present on the upper layer of the paste. Drain pop-up liquid. The paste is dried at a temperature of 60 ° C for 30 minutes or until the loss upon drying is NMT 3.0%.

The chemical reaction of the Diclofenac Sodium Complex - Rubber is indicated:

Potassium Polacrylin Diclofenac Sodium

Diclofenac Sodium Resinate Complex

Stage C: Final Mixing

Weighing and sieving the active substances and the rest of the excipients:

Complex of Diclofenac Sodium with Potassium Polacrilin, hyoscine butyl bromide (3.7 kg)

Crospovidone (6.08 kg)

Aspartame (9 kg)

Dry Mint Flavor (2.83 kg)

All suspended materials are sieved through a 40 mesh strainer. Crospovidone, aspartame, Dry Mint flavor, Rezinat Sodium Diclofenac Complex and Hyoscine butyl bromide with Stage A granules in a blender are mixed for 50 minutes so that a homogeneous powdery mixture is mixed. Stage D: Tableting

The method used to produce tablets is compression using a SMART Kilian 250 rotary tablet press. Compression is carried out in two stages: pre-compression and final compression. Conditions: the main compression force is 8-10 kN, the preliminary compression force is 2-3 kN. The hardness of the tablets is 40 N.

Example 2

Hyoscine butyl bromide 4.0

Diclofenac complex or

diclofenac sodium with potassium

polacriline 60.0

Mannitol 13.8

Aspartame 10.0

Crospovidone 6.4

Polyvinylpyrrolidone K 30 2.0

Flavoring additive 3.4

Silicon Colloidal Dioxide

anhydrous 0.4 Example 3

Hyoscine butyl bromide 4.3

Diclofenac complex or

diclofenac sodium with potassium

polacriline 58.0

Mannitol 14.49

Aspartame 10.5

Crospovidone 6.72

Polyvinylpyrrolidone K 30 2.0

Flavoring Additive 3.57

Silicon Colloidal Dioxide

anhydrous 0.42

Example 4

Study of the effect on the dynamics of disease symptoms and visceral sensitivity in patients with irritable bowel syndrome (IBS).

Material and methods.

The study involved 43 patients who were diagnosed with IBS in accordance with the Rome III criteria: 21 patients were diagnosed with IBS with a predominance of pain and flatulence, 16 - with IBS with a predominance of constipation and 6 - with IBS with a predominance of diarrhea. To all patients before and after therapy with the proposed agent, a colonoscopy was performed; a special study was a balloon dilatation test to determine visceral hypersensitivity. In patients, the intensity of the pain syndrome was evaluated by a known method using a visual analogue scale of abdominal pain and a point score. The tool in example 2 was prescribed a tablet 3 times a day before meals for 2 weeks. The intensity of pain abdominal syndrome decreased in 100% of patients with IBS. The pain syndrome was completely stopped in 80% of patients with IBS with a predominance of constipation and in 50% of patients with a predominance of diarrhea. The severity of constipation decreased by an average of 11%. Almost 90% of patients noted improvement - moderate flatulence or almost not pronounced.

Tablets disintegrate in 20-30 seconds. The maximum plasma concentration is reached on average after 1 hour and is approximately 4.8 ng / ml for butyl bromide hyoscine and 1.5 μg / ml for diclofenac. Industrial applicability

The proposed new tool is an effective drug for the treatment of irritable bowel syndrome. Because the drug showed improved bioavailability, it It can also be successfully used for other disorders of the gastrointestinal tract and pancreaticobiliary system, in which the use of butyl bromide and diclofenac hyoscine is indicated.

Claims

CLAIM

1. The drug is in the form of an orodispersed tablet, characterized in that it contains a combination of Hyoscine butyl bromide and Diclofenac or its sodium salt in combination with Potassium Polacrilin, with a ratio of diclofenac or its sodium salt with potassium polacrilin 1: 2, and pharmaceutically acceptable additives, including Mannitol, Aspartame, crospovidone, Polyvinylpyrrolidone K 30, flavoring agent and silicon dioxide colloidal anhydrous in the following components, wt.%:

Hyoscine butyl bromide 3.7-4.3

Diclofenac complex or

diclofenac sodium with potassium

half-acrylic 58.0-63.0

Mannitol 13.11-14.49

Aspartame 9.0-10.5

Crospovidone 6.08-6.72

Polyvinylpyrrolidone K 30 1.9-2.1

Flavoring additive 2.83-3.57

Silicon Colloidal Dioxide

anhydrous 0.38-0.42

2. A method for producing a medicine according to claim 1, characterized in that mannitol, silicon dioxide, colloidal anhydrous, 20% solution of polyvinylpyrrolidone K 30 are mixed, granulated by spraying in a fluidized bed, the previously prepared diclofenac or diclofenac sodium complex is mixed with potassium polacriline, hyoscine butyl bromide, Crospovidone, aspartame and flavoring, combine the resulting mixture and mix until a homogeneous state is obtained, followed by tableting by compression, including precompression with a force of 2-3 kN and final compression with a force of 8-10 kN.