KR810001231B1 - Process for preparing composition of solid medicine form containing nipedipine - Google Patents

Abstract

Solid forms of nifedipine (I), which have higher bioavailability and lower volume, are prepd. by dissolving or suspending I in a solvent with an appropriate solids (polyvinylpyrrolidinone, methyl cellulose, hydroxy propyl cellulose, etc.) and removing the solvent. Thus, 1 g nifedipine, 2 g poly vinylpyrrolidinone and 1 g Na lauryl sulfate were dissolved in 60 g CHCH3-EtOH (9:1). Spray-drying gave a powder which, on oral administration to dogs, yielded plasma I concns. comparable with those given by a std. I prepn.

Description

Process for Preparation of Solid Formulations Containing Nifedipine

The present invention provides a process for the preparation of a solid preparation composition of nifedipine (4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine), in particular high bioavailability. The present invention relates to a method for producing a solid preparation composition containing nifedipine having a low volume for easy administration.

Nifedipine is known to be useful for developing angina due to its coronary relaxation.

Since it is difficult to predict the onset of angina onset, and sometimes it is necessary to treat the patient on its own, it is recommended that a therapeutic agent used for the treatment of angina should be easily administered and has a fast and sure effect. Particularly preferred. However, since nifedipine has low solubility, oral administration shows low bioavailability and is easily decomposed by light, pharmaceutical preparation of nifedipine is very difficult.

Known so far for the preparation of nifedipine for oral administration are tablets, pills (UK Patent No. 1,173,862) and oral release capsules (US Pat. No. 3,784,684). Among them, tablets and pills were reported to be ineffective due to their low absorption rate (US Patent No. 3,784,684). On the other hand, oral release capsules in which nifedipine solution dissolved in nifedipine solution using a dissolving agent in the oxidizing voxel have a high effect and good bioavailability, but since this is a fluid formulation, the formulation is limited and the manufacturing process is much higher than that of the solid preparation. Complex.

Moreover, nifedipine has low solubility and such oral preparations require large amounts of solubilizers or dissolution aids.

Therefore, this figure is inevitably large, and usually the weight of the oral release capsule (flowable formulation) is 615mg. Special tablets such as large tablets and capsules, ovals, and ovals are used to facilitate taking, but they are difficult to take when they weigh more than 400 mg.

Under these conditions, the study of solid preparations of nifedipine has resulted in the combination of nifedipine and special materials to produce solid formulations containing the same high bioavailability and smaller volume and more easily administerable nifedipine as the flowable formulation.

According to the present invention a solid pharmaceutical formulation composition of nifedipine is a mixture of nifedipine and at least one of (a) polyvinylpyrrolidone, methylcellulose, hydroxy propylcellulose and hydroxyl propylmethyl cellulose as the primary substrate or nifedipine 1 (B) at least one of polyvinyl pyrrolidone, urea, citric acid, mannitol, succinic acid, methylcellulose, hydroxy propylcellulose and amino acids as primary substrates and surfactants, polyethyleneglycols, propylene glycol, as secondary substrates, Mixtures with at least one of glycerol, glycerol fatty acid esters and vegetable oils or mixtures with nifedipine, primary substrate (b), secondary substrates and calcium lactate.

Pharmaceutical formulations and compositions containing nifedipine of the present invention may, if desired, contain colorants, sweeteners, fragrances and diluents.

The present invention uses an amino acid as one of the primary substrate (b) to perform, and the preferred amino acid is threonine, glycine, alanine, cisane, lysine and the like. In this case, any of D-type, L-type, and DL-type may be used. As the surfactant, one of the secondary substrates is used, and examples thereof include low ionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters, polyoxyethylene higher alcohol ethers, polyoxyethylene castor oil derivatives, and the like. There are nonionic surfactants, which are used alone or in combination as appropriate.

In addition, the polyethylene glycol used as one of the secondary substrates in the present invention is preferably a fluid substrate such as PEG 200, PEG 400, PEG 600, and the vegetable oil is sesame oil, corn oil, soybean oil, rapeseed oil. , Olive oil and coconut oil are preferred.

Diluents used with solid formulations include lactose, starch, crystalline cellulose, low-substi-uted hydroxypropyl cellulose, synthetic aluminum silicates, calciumhydrogen phosphate, silicic anhydride, and the like.

The solid preparation composition of the present invention is prepared by the following method. That is, one of nifedipine and one of the primary substrates (a) is dissolved in the organic solvent, or one of the one and two of the primary substrates (b) and the second substrate is dissolved in the organic solvent, or the nifedipine is dissolved in the primary substrate. (b) dissolving or suspending in at least one of the secondary substrates and calcium lactate and an organic solvent or, if necessary, adding a coagulant, sweetener, fragrance and diluent to the solution or suspension and then lyophilizing, heating at atmospheric pressure or reduced pressure. And the organic solvent is removed by a suitable method such as spray drying.

Although the compounding ratio of nifedipine to each substrate depends on the type of substrate, the compound of the primary substrate (a) or (b) preferably has a weight of 20 or less, particularly 1 to 10, with respect to the weight 1 of nifedipine, It is preferable that it is 0.1-10 especially 0.5-5 in weight ratio with silver, and it is preferable that it is 20 or less especially 1-10 in calcium lactate weight ratio.

In order to prepare the pharmaceutical formulation composition of the present invention, a solvent for dissolving nifedipine, the primary substrate (a) or (b), and the secondary substrate is used in an amount necessary for dissolving the components. It is preferable to use an organic solvent such as methanol, ethanol, chloroloam, dichloromethane, or the like, alone or properly mixed, and use 5 times or more of the weight of nifedipine.

In the present invention, the secondary substrate cooperatively increases the solubility of nifedipine in the primary substrate (b) to reduce the compounding ratio of the primary substrate (b). The addition of calcium lactate also increases the compounding ratio of the flowable secondary mass, which will be limited to the small amount needed to produce a solid composition under the calcium lactate subdivision, thereby reducing the compounding ratio of the primary substrate (b). In other words, the required amount of the primary substrate (b) in the case of adding calcium lactate is 1/5 to 1/2 than that in the case of not using it, so that the weight of one tablet or one capsule is reduced to about 150 to 200 mg and is easily administered. You can do it.

The properties of the solid preparation composition according to the present invention vary depending on the substrate to be added, but in any case a clear or solid solution material in which nifedipine is dissolved in a primary substrate (a) or a mixture of primary and secondary substrates (b) and secondary substrates. Is generated. In addition, when calcium lactate is added, the transparent or solid solution material is adsorbed onto the calcium lactate particles.

In the solid preparation composition according to the present invention, nifedipine is slow to decompose and the composition can be stored for more than three years without precipitation of crystals.

The composition of the present invention may be formulated as a powder, granules, tablets, capsules, pills, etc. in a conventional manner. When such tablets, powders, and the like are used, the measurement, preparation of the powder, administration, and the like are easier than the flowable formulations, and the dosage can be appropriately added or decreased.

When calcium lactate is added to the solid composition, the solid composition is very easily crushed and its liquefaction is greatly increased. Therefore, a solid composition containing calcium lactate is particularly useful for nifedipine-containing solid preparations for oral administration such as tablets and powders. Suitable for manufacture

In order to demonstrate the excellent bioavailability, the change in the concentration of nifedipine in the plasma over time after oral administration of the compound is described in the Dodger test example.

Example I

Manufactured in 16-hour fasted succa (12.5 kg in 10.5) Nifedipine is orally administered with a simultaneous 30 mg dose of Example 4, Type 10 and Adalat (trade name) capsules. Blood is collected at 0.5, 1, 2, 4 and 7 hours after oral administration and the drug concentration in plasma is measured by polarized ion test such as dodger.

Nifedipine aqueous solution (0.5ml, 300mg), 0.1N HC1 and 1% NaNO ₂ (0.3ml) expressed in deuterium were added to the plasma sample, and the mixture was incubated at 45 ° C for 1 hour to give 1,4-dihydropyridine ring of nifedipine. Oxidized pyridine homologue. After cooling, 2N-NaOH (0.5ml) was added to the mixture to make an alkali, followed by extraction with benzene (4ml).

The organic layer is evaporated to dryness and ethyl acetate (50 μl) is added to the residue. 1 μl each was injected into a column of gas chromatography-mass spectrometer, and the amount of nifedipine in each sample was measured by measuring the peak height ratio of the pyridine homolog of nifedipine (m / e 298) and nifedipine (m / e 306) expressed in deuterium. Calculate by comparing with standard keb.

This value is for two dogs.

* Plasma concentration time curve region

This value is for 3 dogs ± S.E.

Example II

Four healthy male volunteers (53-70 kg, 25-35 years old) who fasted overnight were orally administered nifedipine with 10 mg doses of Type 20 and Adalat (tradename) capsules simultaneously.

Blood samples are taken at 0.5, 1, 2, 4 and 8 hours after oral administration and the concentration of drug in plasma is measured by polarized ion test.

This value is for ± volunteers ± S.E.

* Plasma concentration time curve region

The manufacturing process of the solid preparation composition of the present invention is as in Dodger [Example.

Example 1

After dissolving 1 g of nifedipine and 10 g of polyvinylpyrrolidone in 50 g of methanol, the solvent is distilled by heating under normal pressure to give a solid product.

Example 2

After dissolving 1 g of nifedipine and 5 g of polyvinylrrolidone in 20 g of a mixture of methanol and carbon tetrachloride in a weight ratio of 2: 3, the organic solvent is distilled by spray drying to give a powdery product.

Example 3

1 g of nifedipine and 20 g of polyvinylpyrrolidone are dissolved in 100 g of methanol, followed by freeze drying of organic solvent and distillation to produce a solid product.

Example 4

After dissolving 1 g of nifedipine, 2 g of polyvinylpyrrolidone, and 1 g of sodium lauryl sulfate in 60 g of a mixture of chloroform and ethanol in a weight ratio of 9: 1, the organic solvent was distilled by spray drying to give a powdery product.

Example 5

Dichloromethane and chloroform having a weight ratio of 1: 1. Dissolve 80 g in 1 g of nifedipine, 20 g of polyvinylpyrrolidone, 0.1 g of polyoxyethylene (60), hydrogenated castor oil, and 5 g of polyethylene glycol 400, and then depressurize the solvent. Distillation under, to fix the product.

Example 6

A solid product is produced by dissolving 1 g nifedipine, 1 g polyethylene glycol 400 and 5 g polyvinylpyrrolidone in 20 g methylene chloride, then heating the solution under reduced pressure to distill the solvent.

Example 7

1 g of nifedipine, 1 g of sodium lauryl sulfate and 5 g of polyvinyl pyrrolidone were dissolved in 60 g of a mixture of chloroform and ethanol in a weight ratio of 9: 1, and 2.5 g of calcium lactate was uniformly dispersed and ground dried. The solvent is distilled off to give a powdery product.

Example 8

10 g of calcium lactate was uniformly dispersed in a solution of 1 g of nifedipine, 5 g of polyethylene glycol 400, and 10 g of polyvinyl pyrrolidone in 30 g of dichloromethane, and then heated under normal pressure to distill the organic solvent to produce a solid product. do. When the solid product is ground in a conventional manner, a powdery product is stored.

Example 9

1 g nifedipine, 1 g sesame oil, 5 g hydroxy propylmethyl cellulose and 0.1 g polyoxyethylene (60), hydrogenated castor oil dissolved in 20 g of a mixture of dichloromethane and methanol in a weight ratio of 8: 2 After 5 g of calcium lactate was uniformly dispersed, the dispersion was heated under reduced pressure to distill the organic solvent to produce a solid product. Grinding the solid product in a conventional manner gives a powdery product.

Example 10

10 g of calcium lactate was uniformly dispersed in a solution of 1 g of nifedipine, 1 g of polyethylene glycol 400 and 5 g of polyvinyl pyrrolidone in 50 g of dichloromethane, and then the dispersion was heated under normal pressure to distill the organic solvent. Is generated. Grinding the solid product in a conventional manner gives a powdery product. 17 g of the obtained powdery product was immediately added with uniform mixing of 2.8 g of corn starch and 0.2 g of magnesium stearate. The mixed powder is divided into 200 mg each and filled into hard gelatin capsule No. 2 using a capsule filling machine.

Example 11

After dissolving 1 g of nifedipine, 0.5 g of glycerol monooleic acid ester and 10 g of methyl cellulose in 70 g of a mixture of dichloromethane and methanol in a weight ratio of 7: 3, 1 g of calcium lactate was uniformly dispersed, followed by spray drying. Distillation of the organic solvent produces a powdery product.

Example 12

1 g of nifedipine, 1 g of glycerol, 3 g of hydroxypropyl cellulose and 5 g of calcium lactate are dissolved in 200 g of methanol, followed by distillation of the organic solvent by Tokyo Drying to produce a solid product. Decomposition of the solid product in a conventional manner gives a powdery product.

Example 13

1 g of nifedipine, 2 g of octyldecyltriglyceride, 5 g of mannitol, and 10 g of calcium lactate are dissolved in 150 g of methanol, and then heated under normal pressure to distill the organic solvent to produce a solid product. Grinding the solid product in a conventional manner gives a powdery product.

Example 14

After uniformly dispersing 8 g of calcium lactate in a solution of 1 g of nifedipine, 1 g of polyoxyethylene trimesyl ether and 5 g of urea in 20 g of methanol, the organic solution was distilled off by heating the dispersion under normal pressure to obtain a solid product. Is generated. Grinding the solid product in a conventional manner gives a powdery product.

Example 15

10 g of calcium lactate was uniformly dispersed in a solution of 1 g of nifedipine, 1 g of corn oil and 5 g of L-threonine in 30 g of methanol, and then the dispersion was heated under reduced pressure to distill the organic solvent. Is generated. Grinding the solid product in a conventional manner gives a powdery product.

Example 16

A solid product is produced by dissolving 1 g of nifedipine, 2 g of propylene glycol, 2 g of citric acid, and 5 g of calcium lactate in 200 g of methanol and distilling the organic solvent by freeze drying. Grinding the solid product in a conventional manner gives a powdery product.

Example 17

10 g of calcium lactate was uniformly dispersed in a solution of 1 g of nifedipine, 5 g of polyethylene glycol 400, and 5 g of polyvinyl birrolidone in 150 g of dichloromethane, and then the organic solvent was distilled by spray drying to obtain a powdery product. Is generated.

Example 18

1 g of nifedipine, 1 g of polyethylene glycol 400 and 5 g of hydroxypropyl methyl cellulose were dissolved in 80 g of a mixture of dichloromethane and methanol in a weight ratio of 7: 3, and 5 g of calcium lactate was uniformly dispersed, followed by spray drying. Distillation of the solvent produces a fine powdery product. To 12 g of the fine powdery product obtained is immediately added 1.8 g of corn starch, 1 g of calcium carboxymethyl cellulose and 0.2 g of magnesium stearate with uniform mixing. The mixture is formulated with a weight of 150 mg using a flat punch of 8 mm diameter.

Example 19

5 g of calcium lactate was uniformly dispersed in a solution of 1 g of nifedipine, 1 g of polyethylene glycol 400 and 5 g of polyvinylpyrrolidone in 30 g of thichloromethane, and then the organic solvent was distilled by spray drying to obtain a fine powdery product. Is generated.

To 11 g of the resulting fine powdery product was immediately added 8 g of crystalline lactose, 3.7 g of calcium carboxymethyl cellulose, 0.1 g of light anhydrous acid and 0.2 g of magnesium stearate with uniform mixing. The mixture was formulated at 230 mg by weight with a flat punch of 8.5 mm diameter.

Example 20

50 g of calcium lactate was uniformly dispersed in a solution of 10 g of nifedipine, 10 g of polyethylene glycol 400, and 50 g of polyvinyl pyrrolidone in 300 g of dichloromethane, followed by mixing with the dispersion and 380 g of lactose. (Iii) granulation by the dog method produces granular powder.

Example 21

5 g of synthetic aluminum silicate is uniformly dispersed in a solution of 1 g of nifedipine, 1 g of polyethylene glycol 400, and 5 g of polyvinyl pyrrolidone in 30 g of dichloromethane, followed by granulation to distill the organic solvent by dry method. This produces a fine powdery product.

Claims (1)

Nifedipine and a mixture of at least one primary (a) substrate of polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose and hydroxy propyl methyl cellulose are dissolved in an organic solvent, or nifedipine and polyvinylpyrrolidone, Primary (b) substrates and surfactants, polyethylene glycol, propylene glycol, glycerol, glycerol fatty acid esters and real oils of at least one of urea citric acid, mannitol, succinic acid, methylcellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose and amino acids Dissolve the mixture with at least one secondary substrate in an organic solvent, or dissolve or suspend a mixture of nifedipine, primary substrate, secondary substrate and calcium lactate in an organic solvent, and then remove the organic solvent if necessary. Preparation of nifedipine-containing solid preparation composition characterized by adding a diluent Way.