JPS6250445B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical dosage form, a process for its production and a package containing this dosage form.

Many drugs are administered orally in the form of solid articles such as tablets, pills, and capsules. in general,
The tablet, pill or capsule must be swallowed orally into the stomach and the drug must be able to be absorbed by the gastrointestinal system. However, in some cases there are problems that make swallowing difficult or not easy. Some patients, particularly pediatric and geriatric patients, can be uncooperative and may spit out the tablet without swallowing it. Similar problems exist when administering drugs to non-human animals in veterinary procedures, where animals may also be uncooperative in ingesting tablets. The present invention seeks to avoid this problem by providing a pharmaceutical dosage form that rapidly disintegrates in the mouth.

Embodiments of the invention dissolve very rapidly in the saliva of the mouth, for example in 1 or 2 seconds, leaving an uncooperative patient with little time to cough up the product.

Accordingly, the present invention provides a pharmaceutical dosage form for oral administration as a solid that is rapidly disintegrable in water, comprising:
It consists of an open matrix network structure with a unit dose of drug substance, which structure provides the pharmaceutical dosage form, which is comprised of a pharmaceutically acceptable water-soluble or water-dispersible carrier material.

"Rapidly disintegrates" means British Pharmacopoeia (BP)
This means that the dosage form disintegrates in water within 10 seconds when tested using the following method similar to the 1973 tablet disintegration test.

Apparatus A glass or suitable plastic tube with a length of 80 to 100 mm, an inner diameter of approximately 28 mm and an outer diameter of 30 to 31 mm, with a disk of rust-proof wire mesh at its lower end in the form of a basket meeting the requirements of a No. 1.70 sieve. .

Has a flat bottom and inner diameter of about 45mm, 36° to 38°C
A glass cylinder containing water to a depth of more than 15 cm at a temperature of .

Place the basket in the cylinder and move it up and down repeatedly until it reaches the center of the cylinder so that the wire mesh breaks the water surface at the highest point, and the upper frame of the basket is just above the water at the lowest point. Hang it on.

Method A pharmaceutical form is placed in a basket and raised and lowered so that complete up-and-down movements are repeated at a rate equal to 30 times per minute. The dosage form is considered to have disintegrated when no particles remain on the wire mesh, which does not allow particles to easily pass through. Such particles should not remain after 10 seconds. The dosage form preferably disintegrates (dissolves or disperses) within 5 seconds.

"Open matrix structure" means a structure of water-soluble or water-dispersible carrier material having pores throughout. This open matrix structure of carrier material generally has a low density. For example, this density is 10 to 200 mg/cc, e.g. 10 to 100 mg/cc.
cc, preferably within the range of 30 to 60 mg/cc.
The density of the dosage form can be influenced by the amount of drug substance or other ingredients incorporated into the article, and may be outside the preferred limits described above for the density of the matrix structure. An open matrix structure, similar in structure to a solid foam, allows liquid to enter and pass through the product through its pores. Permeation by an aqueous medium exposes the carrier material, both inside and outside the product, to the action of the aqueous medium, thereby rapidly disintegrating the structure of the carrier material. This open matrix structure is porous and increases the disintegrability of the product as compared to conventional solid shaped pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and pessaries. Due to the rapid disintegration, the medicinal substance contained in the matrix is rapidly released.

The carrier materials used in the products of the invention are either water-soluble or water-dispersible materials that are pharmaceutically acceptable, inert towards the drug substance, and capable of forming open matrix structures that can rapidly disintegrate. be. It is preferred to use water-soluble materials as carrier materials, since the matrix disintegrates fastest when the product is placed in an aqueous medium.
It has been found that a particularly advantageous carrier can be formed from polypeptides such as gelatin, especially partially hydrolyzed (eg by heating in water) gelatin. For example, gelatin is produced by preparing an aqueous solution of gelatin in an autoclave at about 120°C.
Partial hydrolysis can be achieved by heating for up to 2 hours, such as from about 5 minutes to about 1 hour, preferably from about 30 minutes to about 1 hour. The hydrolyzed gelatin is preferably used at a concentration of about 1 to 6% weight/volume, most preferably 2 to 4%, such as about 3%. Instead of partially hydrolyzed gelatin, other carrier materials may be used, such as hydrolyzed dextran, dextrin and polysaccharides such as alginates (for example sodium alginate), or mutual mixtures of carriers, or also carriers with polyvinyl alcohol, polyvinylpyrrolidine or gum arabic. Mixtures with other carrier materials can also be used.

The pharmaceutical dosage form according to the invention can be used for the administration of a wide range of pharmaceutical substances. As used herein, "medicinal substance" includes not only pharmaceuticals administered to humans and animals, but also contraceptives (particularly oral contraceptives). Typical pharmaceuticals that can be administered according to the present invention include, for example, drugs for treating cardiovascular disorders;
For example digoxin; oral vaccines; enzymes; anti-angina drugs (e.g. glyceryl trinitrate); peripheral vasodilators and antihypertensives (e.g. indolamine); vasoconstrictors (e.g. ergotamine); analgesics (e.g. meptazinol, pentazocine) hypnotics; dedicated and secondary tranquilizers (e.g. lorazepam, oxazepam, temazepam); antidepressants (e.g. cyclazindole); anticonvulsants (e.g. clonazepam); CNS stimulants (e.g. pemoline);
Muscle relaxants (e.g. orphenandrine); neuromuscular agents (e.g. pyridostigmine); sex hormones and oral contraceptives (e.g. ethinyl estradiol, norgestrel); corticosteroids (e.g. prednisolone); local anesthetics; anti-inflammatory agents ( drugs that act on the uterus (e.g. hyoscine butyl bromide); sperm-destroying agents (e.g. nonoxynol-
9); includes anti-allergic agents (eg triprolidine); and agents that alleviate toxicity and metabolic dysfunction (eg methysergide). This pharmaceutical dosage form is particularly useful for oral administration of drugs.
Although this dosage form can be used to administer drugs that are normally absorbed via the gastrointestinal tract, it is also useful for administering drugs (e.g. nitroglycerin) by the oral route, as such drugs can be used in the present invention. This is because it can be absorbed very rapidly with the use of

The dosage forms of the invention may contain other ingredients in addition to the pharmaceutical substance. For example, the pharmaceutical dosage forms of the invention can contain pharmaceutically acceptable auxiliaries. Such auxiliaries include, for example, colorants, flavoring agents, preservatives (eg, bacteriostatic agents), and the like.

The invention also provides a method for manufacturing this pharmaceutical dosage form.
i.e., a process for the preparation of pharmaceutical dosage forms for oral administration as solids, which are rapidly disintegrable in water, from a solution in which the solvent is a medicinal substance and a pharmaceutically acceptable water-soluble or water-dispersible carrier material. sublimation of the solvent from the composition, which is in a solid state in a mold corresponding in size and shape to that of a pharmaceutical dosage form, to create an open matrix network of carrier material with the pharmaceutical substance; provide the above method, which can be rapidly disintegrated by water.

Preferably, sublimation is carried out by freeze-drying a composition consisting of a solution of the drug substance and carrier substance in a solvent. The composition may contain additional ingredients as described above. The solvent is preferably water, but may contain a co-solvent (eg tertiary butyl alcohol) to improve the solubility of the drug substance. The composition may also contain a surfactant such as tween 80 (polyoxyethylene (20) sorbitan mono-oleate). Surfactants help prevent the freeze-dried product from sticking to the mold surface. This may also aid in dispersion of the drug substance.

The mold consists of a series of cylindrical or other shaped depressions, each size corresponding to the desired molded article size. For example, the mold may be a metal plate or a sheet of film material with indentations.

In one embodiment, the mold consists of a metal plate (eg, an aluminum plate) with one or more indentations. A preferred method using such a type is to
The mold is cooled with a refrigerant (eg liquid nitrogen or solid carbon dioxide). When cooling the mold, a predetermined amount of water containing the carrier substance, pharmaceutical substance and other desired ingredients is charged into this cavity. Once the contents of the wells are frozen, the mold is subjected to vacuum and, if desired, controlled heat is applied to aid sublimation. The pressure may be less than about 4 mm Hg. 0.3mmHg
Preferably, a pressure of less than 0.1 to 0.2 mm is used. The lyophilized product can then be removed from the mold cavity and stored for future use, eg, in an airtight jar or other suitable storage container.

Another method for manufacturing the dosage form is described in Japanese Patent Application No. 60-239251, which is a divisional application in this case.

The following examples illustrate the invention: Example 1 (a) Preparation of a hydrolysed gelatin solution British Pharmacopoeia gelatin 30.00 g Purified water Amount to bring the total volume to 1000.00 ml While heating the gelatin and stirring constantly Soluble in water. The resulting solution is heated in an autoclave at 121° C. (15 psi) for 1 hour. Allow the solution to cool to room temperature.

(b) Manufacture of pharmaceutical dosage form Lorazepam 1.00 g Colorant (FDC Yellow No. 5) 0.25 g Orange flavor (Norda spray drying) 0.5 g Gelatin solution Amount to bring the total volume to 1000.00 ml 75 cylindrical depressions ( An aluminum mold (each depression having a diameter of about 0.5 cm and a depth of 1 cm) is cooled to about -192°C in liquid nitrogen in a stainless steel pan. Mix the lorazepam color and flavor with the gelatin solution and, while continuing to mix, inject 1/2 ml of the mixture into each well with a hypodermic syringe. After freezing the contents of each well, the mold was placed in a vacuum chamber at room temperature and 0.3 mmHg
Apply vacuum overnight. The lyophilized pharmaceutical forms containing 0.5 mg of lorazepam each are removed from the wells and stored in airtight jars.

This pharmaceutical dosage form disintegrates rapidly when placed in the mouth, for example in less than 2 seconds.

Example 2 Nitroglycerin instead of 1.00g of lorazepam
The method of Example 1(b) is repeated using 2.00 g and appropriate pharmaceutically acceptable colorants and flavors to make pharmaceutical dosage forms each containing 1.00 mg of nitroglycerin.

EXAMPLE 3 The method of Example 1(b) is repeated using 2.00 g of digoxin in place of 1.00 g of lorazepam and appropriate pharmaceutically acceptable colorants and flavors, each containing pharmaceutical dosage forms containing 1.00 mg of digoxin. Create.

Example 4 Ergotamine 2.00g instead of lorazepam 1.00g
repeating the method of Example 1(b) using and using appropriate pharmaceutically acceptable colorants and flavors;
Pharmaceutical dosage forms are prepared, each containing 1.00 mg of ergotamine.

Example 5 Lorazepam 5g Tween 80 [polyoxyethylene (20) sorbitan monooleate] 0.5g sucrose 30g Gelatin solution [from Example 1(a)]
Volume to make the total volume 1000ml Approximately 220 × 150 cylindrical depressions (each depression has a diameter of approximately 1.4cm and a depth of 0.7cm)
A PVC sheet with a size of 330 mm is cooled with solid carbon dioxide. Mix lorazepam, Tween 80 and sucrose (flavor) with the gelatin solution and place 0.5 ml of this solution into each well while continuing to mix. After freezing the contents of the well, the PVC sheet is immediately placed in a vacuum chamber and a vacuum of approximately 0.1 mmHg is applied for 8 hours. Each indentation is 2.5mg of lorazepam
Contains a pharmaceutical dosage form containing. This dosage form disintegrates rapidly when placed in the mouth, within 1 to 5 seconds.

Example 6 Lorazepam 3.33 g Sodium alginate 15 g Dextran (molecular weight approx. 40000) 35 g Dextrose 17.5 g Distilled water Amount to bring the total volume to 1000 ml 150 cylindrical depressions (each depression has a diameter of approximately 1.4 cm and a depth of 0.7 cm) having about 220×
A PVC sheet with a size of 330 mm is cooled with solid carbon dioxide.

Sodium alginate 15g, dextran 35g
3.33 g of lorazepam are suspended in water containing 17.5 g of dextrose with the aid of ultrasonic vibrations. Place 0.75 ml of this suspension into each well. Example 5
The contents of this well are freeze-dried by the method described in . Each pharmaceutical dosage form contains 2.5 mg of lorazepam.

Example 7 Lorazepam 3.33 g Dextrin 50 g Polyvinylpyrrolidine 30 g Tween 80 0.2 g Distilled water Amount to bring the total volume to 1000 ml A PVC sheet similar to that in Example 5 is cooled with solid carbon dioxide. A mixture of the above compositions was prepared in a manner similar to that of Example 6, and 0.75 ml of the mixture was
Place it in each cavity of the PVC sheet. The contents of this well are lyophilized in the manner described in Example 5. Each pharmaceutical dosage form contains 2.5 mg of lorazepam.

Example 8 Lorazepam 3.33g Polyvinyl alcohol (molecular weight approx. 1400) 20g Polyvinylpyrrolidine 20g Cane sugar 30g Tween 80 0.2g Distilled water Amount to bring the total volume to 1000ml A PVC sheet similar to that in Example 5 is cooled with solid carbon dioxide.

20g of polyvinyl alcohol and about 500ml of hot distilled water
This solution is then cooled. 20g polyvinylpyrrolidine, 30g sucrose and Tween 80
Add 0.2 g of lorazepam and shake the mixture until all solids are dissolved. Add 3.33 g of lorazepam;
Disperse with the help of ultrasonic vibrations. Adjust the final volume of this solution to 1000 ml with distilled water.

Using the method described in Example 5, 0.75 ml of this solution was
Add to each cavity of the PVC sheet and freeze dry the contents of this cavity. Each pharmaceutical form is lorazepam
Contains 2.5mg.

Example 9 Lorazepam 3.33g Gum Arabic 20g Cane sugar 30g Polyvinylpyrrolidine 30g Tween 80 0.2g Distilled water Amount to bring the total volume to 1000ml A PVC sheet similar to that in Example 5 is cooled with solid carbon dioxide.

Place 20g of gum arabic in a dry 1000ml measuring flask. Add about 10ml of absolute alcohol and shake the flask to moisten the gum arabic powder. Add 500 ml of distilled water and shake to produce a homogeneous solution. Add 30g of sucrose, 30g of polyvinylpyrrolidine, 0.2g of Tween 80 and lorazepam to this solution.
3.33g is dispersed with the help of ultrasonic vibrations. Make the final volume to 1000 ml with distilled water. 0.75ml of this composition
Place it in each cavity of the PVC sheet. The contents of this well are freeze-dried by the method described in Example 5. Each pharmaceutical dosage form contains 2.5 mg of lorazepam.

Claims (1)

[Scope of Claims] 1 Gelatin, dextrin, hydrolyzed dextran or alginate, or a mixture of one or more of the above substances with polyvinyl alcohol, polyvinylpyrrolidine or gum arabic, or a mixture of polyvinyl alcohol and polyvinylpyrrolidine, or a mixture of gum arabic and polyvinyl comprising a network of pharmaceutically acceptable water-soluble or water-dispersible polymeric carrier materials selected from mixtures with pyrrolidine, the network containing a unit dose of the drug substance and having a density of 10-200 mg/ml. A solid pharmaceutical dosage form for oral administration, characterized in that: 2. A composition consisting of a pharmaceutical substance, a pharmaceutically acceptable water-soluble or water-dispersible polymeric carrier material, and a solvent for the carrier material is frozen in a mold corresponding to the size and shape, and the solvent is removed from this frozen composition. Let it sublimate,
It consists in creating a network of carrier materials containing the medicinal substance, the carrier material being gelatin, dextrin, hydrolysed dextran or alginate, or a mixture of one or more of the above substances with polyvinyl alcohol, polyvinylpyrrolidine or gum arabic, or polyvinyl alcohol. and polyvinylpyrrolidine or a mixture of gum arabic and polyvinylpyrrolidine, which is rapidly disintegrable in water and is orally administered as a solid.