JPS589082B2 - Manufacturing method of small granules - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for manufacturing a drug.

More specifically, the present invention relates to a method for producing small granules in which the residence time of active ingredients in the stomach is improved.

There are various medicines and veterinary medicines that exhibit stronger medicinal effects due to prolonged residence time in the stomach, and this tendency is particularly noticeable in medicines and veterinary medicines that act in the stomach.

Conventionally known preparations intended to prolong gastric residence time include tablets and capsules mixed with hydrocolloids.

However, in reality, these drugs hardly have a sustained gastric residence time.

As a result of intensive research in view of the current situation, the present inventors prepared small particles containing a water-soluble polymeric substance that exhibits high viscosity in the presence of water as an active ingredient, and further disintegrated the small particles in the stomach. The present inventors discovered that coating with a degradable coating agent prolongs the residence time of the active ingredient in the stomach, leading to the completion of the present invention.

That is, the present invention involves making small particles of a drug containing an active ingredient and a water-soluble polymer substance that exhibits high viscosity in the presence of water, and then coating the drug with a coating agent for disintegrating in the stomach, thereby dissolving the active ingredient in the stomach. This invention relates to a method for producing small granules with improved residence time.

The active ingredient used in the present invention may be any drug or veterinary drug that preferably remains in the stomach for a long time.

Such active ingredients include, for example, anti-ulcer drugs such as anti-pepsin drugs, antacids, and anticholinergic drugs that can act in the stomach in small amounts or have medicinal effects when retained in the stomach in small amounts; vitamin B2 + vitamin B ] 2; antihistamines such as chlorpheniramine; and neurotropic drugs such as benzodiazepines. Particularly preferred are anti-ulcer agents (anti-pepsin drugs).

Preferred anti-pepsin drugs include oligopeptide anti-pepsin drugs, such as pepsinostreptins, pepstatins, and S-PI (Agricultural Biological Chemistry, 35, 1310 (1971)).

The water-soluble polymeric substances exhibiting high viscosity in the presence of water used in the present invention include those whose 5-band water solubility shows a viscosity of 100 centipoise or more, preferably 200 centipoise or more at 25°C, Specifically, alkali metal salts of polyacrylic acid (such as sodium salts), preferably those having a molecular weight of 200,000 or more, and polyethylene glycols preferably having a molecular weight of 100,000 or more are mentioned.

The gastrically disintegrating coating agent used in the present invention may be any coating agent that disintegrates in the stomach, such as one that disintegrates in the stomach, or one that disintegrates by creating cracks.

Examples of such coating agents include those that are soluble in organic solvents (preferably one that dissolves 1 g or more in 100 ml of solvent) and have a melting point of 35 to 65°C, preferably 37 to 45°C. Examples include glycerin monostearate, spermaceti, wood wax, beeswax, carbowax (molecular weight 1,500 to 20,000), paraffin wax, etc.

In the method of the present invention, first, an active ingredient and a polymeric substance exhibiting high viscosity in the presence of water are made into small particles by a method known per se, and the small particles thus obtained are applied to a coating agent for disintegration in the stomach by a method known per se. This is done by coating.

When preparing the small particles, excipients (for example, lactose, mannitol, refined white sugar, sorbitol, corn starch, etc.), disintegrants (carboxymethylcellulose calcium, crystalline cellulose, etc.), binders (hydroxypropyl cellulose, dextrin, etc.) may be added as desired. , and other adjuvants may be added.

Alternatively, the active ingredient may be adsorbed in advance on a porous adsorbent.

Any porous adsorbent may be used as long as it can easily adsorb the active ingredient and easily release the adsorbed active ingredient on the back.

A desirable porous injection adsorbent is, for example, 100mg/
50 mg/g or more, preferably 200 mg/g or more, and when gently stirred in the collected gastric juice under conditions of 37°C, 50 mg/g or more is absorbed within 0.5 to 2 hours, preferably 0.5 to 1 hour. Examples include those that release more than 10% of active ingredients.

Particularly preferred examples of such porous injection adsorbents include:
Examples include activated carbon and porous polystyrene.

Coating of small particles with a gastrically disintegrating coating agent is usually carried out by dissolving one or more of the coating agents in an organic solvent (eg, alcohol, trichlene, dichloroethane, etc.) and using a method known per se.

The thickness of the coating layer formed by the coating agent varies depending on the type of active ingredient, the type of polymer substance exhibiting high viscosity in the presence of water, etc., but it is usually 1 to 100 μm, preferably 1 to 10 μm. .

Prior to coating with the gastro-disintegratable coating, the pellets may be pre-coated with a silicic acid compound.

The silicic acid compound is preferably a silicic acid compound that does not have a water molecule layer in the interlayer position of the crystal. Examples of such compounds include light anhydrous silicic acid, talc, synthetic aluminum silicate, synthetic magnesium aluminate metasilicate, etc. Of these, light silicic anhydride is particularly preferred.

The desirable particle size of the small granules thus produced is usually 150
It is 0-10μ, particularly preferably 500-70μ.

Reference example 1 Capsule formulation (l capsule) Pepsinostreptin 50 (mg) lactose
200 Magnesium stearate 0.4 Production method Pepsinostreptin, lactose and magnesium stearate were mixed homogeneously, and this mixture was filled into No. 2 capsules to prepare capsules.

Gastric Retention Test A group of three male beagle dogs (body weight approximately 10 kg) was administered one capsule together with 15 ml of water under fasted conditions.

Three hours after administration, bentobarbital was intravenously injected for anesthesia.

A gastric catheter was inserted under anesthesia, the stomach was washed with a buffer solution, and the content of vepsinostreptin in the whole lavage fluid was measured.

It has been confirmed in another test that the recovery rate of vepsinostreptin from the stomach of beagle dogs using this method is at least 90 times higher.

Results Three hours after administration, only one of the six beagle dogs had 0
．． 9 mg of vepsinostreptin was found, and the remaining 5
My head didn't recognize it at all.

(1/6: 3 hours) Reference example 2 Tablet prescription (1 tablet) Pepsi Nostrin 50 (mg) Lactose
150 Polyethylene glycol 100 (molecular weight 600,000) Carboxymethyl cellulose calcium 200 Manufacturing method Pepsinostreptin, lactose and polyethylene glycol (molecular weight 600,000) were mixed homogeneously, and an ethanol solution was added to granulate.

After drying the granules, carboxymethylcellulose calcium was added thereto and mixed, followed by pressure molding to form tablets.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

However, the amount retained in the stomach was determined 2 hours after administration of the preparation.
(Dose of formulation: 1 tablet) Results: Two hours after administration, no pepsinostreptin was detected in any of the six animals.

(0/6: 2 hours: Reference example 3 Fine granule formulation (500mg) Pepsinostreptin 50 (mg) Lactose
445 Hydroxyglobil cellulose 5 Production method Pepsinostreptin and lactose were mixed homogeneously, and hydroxyglobil cellulose dissolved in water was added thereto and granulated.

The granulated material was dried and passed through a No. 32 sieve to obtain a fine granule.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

(Dosage of the preparation: 500 mg) Results: Three hours after administration, pepsinostreptin was observed in 5 of the 9 dogs, and the average amount of pepsinostreptin retained in the 5 dogs was 0.
．． It was 1 mg.

Reference Example 4 Fine Granule Formulation (500 mg) Pepsinostreptin 50 (n9) Sodium Alginate 50 Lactose 400 Production Method Pepsinostreptin, sodium alginate and lactose were mixed homogeneously and ethanol was added to granulate the mixture.

The granulated product was dried and passed through a No. 32 sieve, which was used as a fine granule.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

(Dose of formulation: 500 mg) Results: Pepsinostreptin was observed in one of the three animals 3 hours after administration, and the average amount of pepsinostreptin retained in each animal was 0.3 mg.

Example 1 Fine granule formulation (600 mg) Pepsinostreptin 50 (mg) Sodium polyacrylate 300 Lactose 250 Glyceryl monostearate Micro-production method Pepsinostreptin, sodium polyacrylate and lactose are mixed homogeneously, and water is added to the mixture. was added and granulated.

After drying the granules, a coating was applied to them by spraying glyceryl monostearate dissolved in ethanol.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

The amount retained in the stomach 4 hours after administration of the preparation was also determined.

(Dose of formulation: 600 mg) Results Three hours after administration, an average of 42 mg of vepsinostreptin was observed in all three animals.

(3/3: 3 hours) Another 4 hours, 2 hours for all 3 animals.
．． 3 mg of vepsinostreptin was observed.

(3/3: 4 hours) Example 2 Fine granule formulation (1 g) Pepsinostreptin 50 (mg) Sodium polyacrylate 690 Light anhydrous silicic acid 260 Glyceryl monostearate Micro-production method Pepsinostreptin, sodium polyacrylate and A reduced amount of light silicic anhydride was homogeneously mixed, and ethanol was added to the mixture for granulation.

The remaining light anhydrous silicic acid was further added to the granulated product, mixed, and granulated again with ethanol.

After the granules were dried, glyceryl monostearate dissolved in ethanol was sprayed onto them to form a coating.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

The amount retained in the stomach 4 hours after administration of the drug preparation was also measured.

(Dose of formulation: 1 g) Results Three hours after administration, an average of 4.6 mg of vepsinostreptin was observed in all six animals.

(6/6: 3 hours) Also, 4 hours after administration, average of 2 in all 6 animals.

8 mg of vepsinostreptin was found.

(6/6: 4 hours) Example 3 M granule formulation (1 g) Pepsinostreptin 50 (m9) Magnesium oxide 150 Atropine sulfate 1.5 Sodium polyacrylate 600 Lactose 198.5 Beeswax Micro-produced pepsinostreptin, Magnesium oxide, atropine sulfate, sodium polyacrylate, and lactose were mixed homogeneously, and ethanol was added to granulate the mixture.

After drying the granules, beeswax dissolved in triclene was sprayed onto the granules to form a coating, and the mixture was passed through a No. 32 sieve to obtain fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

The amount retained in the stomach 4 hours after administration of the preparation was also determined.

(Dose of formulation: 1 g) Results Three hours after administration, an average of 4 mg of vepsinostreptin was observed in all three animals.

(3/3: 3 hours) Also, 4 hours after administration, an average of 2 mg of vepsinostreptin was observed in all three animals.

(3/3: 4 hours) Example 4 Fine granule formulation (700 mg) Pepsinostreptin 50 (rn) Polyethylene glycol 350 (molecular weight 4 million) Lactose 300 Paraffin wax Micro-process pepsinostreptin, polyethylene glycol (molecular weight 4 million) and lactose were mixed homogeneously, ethanol was added thereto, and the mixture was granulated.

After drying the granules, a coating was applied to them by spraying paraffin wax dissolved in triclene.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

The amount retained in the stomach within 4 hours after administration of the preparation was also determined.

(Dose of formulation 700~) Results Three hours after administration, an average of 4.2 mg of vepsinostreptin was observed in all six animals.

(6/6: 3 hours) Furthermore, an average of 1.9 mg of pepsinostrebutin was observed in all 6 animals 4 hours after administration.

(6/6: 4 hours) Example 5 Prescription pepsinostreptin 50 (n9) Sodium polyacrylate 200 Lactose 150 Light anhydrous silicic acid 100 Glyceryl monostearate Micro-production method Pepsinostreptin, sodium polyacrylate and lactose are homogenized The mixture was mixed, ethanol was added thereto, and the mixture was granulated.

Light silicic anhydride was further added to the granulated product, and the mixture was again granulated with ethanol.

After the granules were dried, a coating was applied to them by spraying glyceryl monostearate dissolved in ethanol.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

The amount retained in the stomach 4 hours after administration of the preparation was also determined.

(Dose of formulation: 500 mg) Results Three hours after administration, an average of 3.8 mg of vepsinostreptin was observed in all three animals.

(3/3: 3:00 p.m.) Also, 4 hours after administration, an average of 2.2 mg of pepsinostreptin was observed in all three animals.

(3/3: 4 hours) Leprosy case 6 Prescription pepsinostreptin 50 (ru) activated charcoal
100 Polyethylene glycol 300 (Molecular weight: 4 million) Lactose 150 Beeswax Micro-production method Pepsinostreptin was dissolved in water, activated carbon was added thereto, and the mixture was stirred.

After confirming that pepsinostreptin was adsorbed on the activated carbon, the activated carbon was filtered and dried.

The obtained activated carbon and polyethylene glycol (molecular weight 40
0,000) and lactose were mixed homogeneously and water was added to granulate the mixture.

After drying the granules, beeswax dissolved in ethanol was sprayed onto them to form a coating.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

(Dosage of formulation 600~) Results Three hours after administration, an average of 4n9 vepsinostreptin was observed in all three animals.

(3/3: 3 hours) Example 7 Prescription (500 mg) Sodium riboflavin phosphate 50 (mg) Hum (vitamin B2) Sodium polyacrylate 200 Lactose 250 Paraffin wax Micro-production method Sodium riboflavin phosphate, sodium polyacrylate and lactose were mixed homogeneously, ethanol was added thereto, and the mixture was granulated.

After drying the granules, a coating was applied to them by spraying paraffin wax dissolved in triclene.

Those that passed through a No. 32 sieve were used as fine granules.

Gastric retention test The test was conducted in the same manner as in Reference Example 1.

(Dose of formulation: 500 mg) Results Three hours after administration, an average of 41 m9 of sodium riboflavin phosphate was observed in all three animals.

(3/3: 3 hours)

Claims (1)

[Claims] 1. A drug containing an active ingredient that preferably remains in the stomach for a long time and a water-soluble polymer substance that exhibits high viscosity in the presence of water is formed into small particles, and then coated with a coating agent for disintegration in the stomach. A method for producing small granules in which the residence time of an active ingredient in the stomach is prolonged, characterized by: