KR880000969B1 - Process for preparing a solid shapes article - Google Patents

Abstract

Pharmaceutical dosage forms which quickly dissolve in H2O are prepd. by freezing a soln. contg. partially hydrolyzed gelatin, drug, and other adjuvants in a mould by passing cooling media over the mould and subliming the solvent to produce a network of the gelating carrying the drug. Thus, a suspension of 40g oxazepam, 30g mannitol, and 0.5g Tween 80 in 1 l of 3% hydrolyzed gelatin soln. are poured to PVC blister trays in 0.75ml portions and subjected to liq. N2. The portions in the blister trays are freezedried to give the dosage forms which disintegrate in <2 sec. when taken orally.

Description

Manufacturing method of solid molded product

The present invention relates to a method for producing a solid molded article containing a unit amount of a chemical measured in advance. In particular, the present invention relates to a method for producing a product that can be decomposed by water at 20 ℃ within 5 seconds.

The present invention can be decomposed by water at 20 ° C. within 5 seconds, filling a mold with a composition consisting of a pre-measured unit amount of chemicals and a partially hydrolyzed gelatin solution, and filling the template with a gaseous cooling medium. After passing through to freeze the composition in the template, the solvent is sublimed from the frozen composition to produce a net partially hydrolyzed gelatin containing chemicals.

The products obtained according to the invention are useful for a wide variety of different applications, particularly when one wishes to administer, prepare or use a unit of measure in advance of a chemical. For example, certain chemicals that must be used in the form of solutions or suspensions, but are difficult or hazardous to transport in this form, are converted into solid form by the process of the present invention, and the user can add it to an aqueous medium to determine the amount of chemical It is possible to produce the desired solution or dispersion containing the substance. The chemical may also be such a chemical reagent that can add a product of the process of the invention to a known amount of aqueous liquid to produce a standard liquid mixture that can be used, for example, in chemical analysis. The chemical may also be a diagnostic compound which is preferably added to a biological sample (eg blood, urine) in order to determine the amount of certain components present in the sample. However, it is preferred that this chemical is a pharmaceutical substance and that the solid molded product containing a premeasured unit amount of the pharmaceutical substance is in pharmaceutical dosage form.

Pharmaceutical dosage forms produced by the process of the invention are particularly suitable for oral administration. In oral administration, the pharmaceutical dosage form generally degrades rapidly (eg within 1 to 2 seconds) in the oral cavity, so this dosage form is particularly advantageous as a means for administration to humans and also for the administration of animals. Dosage forms produced by the process of the present invention may also be used as tablets, pills or capsule substitutes, particularly in patients who have difficulty swallowing conventional dosage forms.

The first step in the process of the present invention is to fill the template with components. For example, the template may be a depression on a metal plate (eg an aluminum plate). The metal plate may comprise one or more recesses, each recess having a size and shape corresponding to the desired size of the molded article. However, the template is preferably a recess in the sheet of thin film material. This thin film material may include one or more recesses. This thin film material may be similar to that used in conventional blister packaging used to package drugs such as oral contraceptives. For example, the thin film material may be made of a thermoplastic material having recesses formed by heat. Preferred thin film materials are polyvinyl chloride thin films. Stacks of thin film materials may also be used.

Partially hydrolyzed gelatin can be prepared by heating a gelatin solution in water (eg, heating in a high pressure steam cooker at about 120 ° C. for less than 2 hours (eg, about 30 minutes)). Hydrolyzed gelatin is preferably used at a concentration of about 1 to 6% (weight / volume), most preferably 2 to 4% (eg about 3%).

In addition to chemicals and hydrolyzed gelatin, the compositions may also contain other additives. For example, in the manufacture of pharmaceutical dosage forms, the composition may contain pharmaceutically acceptable auxiliaries (eg colorants, fragrances, preservatives, etc.). The composition may also contain auxiliary ingredients in the production of molded articles. For example, the composition may contain a surfactant (eg, Tween 80 (polyoxyethylene 20) sorbitan mono oleate) to aid in the dispersion of the chemical. The composition may also contain ingredients such as fillers (eg mannitol, sorbitol) to improve the physical properties of the molded article.

Although water is preferred as the solvent of the composition, co-solvents such as alcohols may be used together to improve the solubility of chemicals.

Preferred amounts of the composition (eg 0.3 ml to 1.0 ml) can be filled in the template, for example using an automatic filling machine.

The gaseous cooling medium is passed through the template to freeze the composition contained in the template. Passing the gaseous cooling medium on a fixed template, moving the template in the gaseous cooling medium, or preferably moving both the template and the gaseous cooling medium. For example, in a preferred embodiment, the template containing the composition is moved in one direction in the chamber and the gaseous cooling medium is dragged or negative in the opposite direction in the chamber. For example, liquid nitrogen can be injected into the chamber. Liquid nitrogen is vaporized and drawn into the chamber by the fan in the direction opposite to the template in which gaseous nitrogen is moved. By controlling the injection speed of the liquid nitrogen, the speed of the fan, and the transport speed of the template, a preferable freezing rate can be obtained. Liquid nitrogen can be replaced with other liquefied gases (eg liquid argon or fluorinated hydrocarbons).

Once the composition is frozen, the solvent can be sublimed therefrom. If necessary, the freezing composition may be stored in the refrigerator prior to the sublimation process.

Sublimation can be carried out by subjecting the in-plate freezing composition to reduced pressure in a homogeneous dryer and, if necessary, controlled heating to assist sublimation. The pressure may be about 4 mmHg or less, for example 0.3 mmHg or less, for example 0.1 to 0.2 mmHg or 0.05 mmHg or less. In lyophilizers the onset temperature is as high as, for example, 60 ° C., which can be reduced (eg to 50 ° C.) as the temperature of the homogeneous composition increases.

After the sublimation process, the molded product can be recovered from the metal plate and stored for later use. Preferably, when the template is one of many recesses in the thin film material, the wrapper may be attached to the thin film material to make the package surrounding the molding material. The wrapping paper is preferably an aluminum foil or an aluminum foil laminate that can be attached to the thin film material around the recess by, for example, a heat sensitive adhesive. The wrapping paper is desirable for the user to peel off the wrapping paper from the thin film material and attach it to the thin film material so that the dosage form can be exposed at the recess.

By the sublimation step, a molded article consisting of net-shaped partially hydrolyzed gelatin containing chemicals is produced. This net-like product, similar in structure to a solid foam, allows liquid to enter the product into the gap and allow it to penetrate inside. When the aqueous medium penetrates, both the inside and outside of the molded article are acted upon by the aqueous medium to quickly break down the net material. Using the standard tablet digestion apparatus described in British Pharmacopoeia, 1980, Volume 2 Annex X IIA, the degradation time of the product is measured by observing whether it can be degraded by water within 5 seconds at 20 ° C, with a standard 2.00 mm Use stainless steel 40 mesh instead of wire mesh. The sample is placed in a dry test tube on the surface of the water and the device is started to soak the sample in water at 20 ° C. The sample must be dispersed on the liquid surface and any solid residue must pass through the 40 mesh sieve within 5 seconds.

The following examples illustrate the invention in detail.

Example 1

Pharmaceutical Dosage Form Containing 30mg Oxazepam

Furtherance :

Oxazepam 30mg

Twin 80 BPC 0.375mg

Mannitol BP 22.5mg

Add 3% hydrolyzed gelatin to 0.75 ml.

Suspend 30 g of gelatin powder in 800 ml of cold distilled water in a 1 L flask and autograde at 121 ° C. for 50 minutes to prepare 3% hydrolyzed gelatin. Once cooled, distilled water is added to a final volume of 1 liter.

Suspension 40 g of oxazepam was dissolved in 3% hydrolyzed gelatin dissolved in 30 g of mannitol and 0.5 g of Tween 80 using ultrasound for 5 minutes and the suspension was brought to 1 L with 3% gelatin solution. 0.75 ml of the suspension is placed in a hole in a polyvinyl chloride blister tray using an automatic filler. Place the tray in the carrier that passes along the tunnel. Liquid nitrogen is injected at the other end of the tunnel. The liquid nitrogen is vaporized and the fan in the tunnel blows the nitrogen gas cooling medium in the opposite direction as the tray on the carrier moves. The rate of injection of liquid nitrogen, the speed of the fan and the speed of the carrier are adjusted to allow the composition in the brister to freeze as the tray passes through the tunnel.

Blister trays containing the freeze composition are transferred to a freeze dryer. The pressure is adjusted to 0.5 mm Hg and the shelf temperature in the freeze dryer is fixed at 60 ° C. for 1 hour 30 minutes and then lowered to 40 ° C. After 6 hours the tray is removed from the freeze dryer. The peelable aluminum foil is then wrapped and sealed around the recess containing the pharmaceutical dosage form. Pharmaceutical dosage forms degrade rapidly (eg, within 2 seconds of oral administration). When tested by the process described above, they are decomposed by water within 5 seconds at 20 ° C.

Similar pharmaceutical dosage forms containing the following active ingredients can be prepared:

Oxazepam 15mg and 50mg Bendrofluazide 5mg

Lorazepam 1,2,2.5 and 4mg cyclopentthiazide 0.5mg

Temazepam 10 and 20 mg isosorbide dinitrate 2.5,5 and 10 mg

Lormetasepam 1mg Indomethacin 25 and 50mg

Pruceamide 40mg prochlorperazine maleate 50mg

Claims (5)

A composition consisting of a pre-measured amount of a chemical and a partially hydrolyzed gelatin solution is filled into a template, a gaseous cooling medium is passed through the template to equalize the composition in the template, and then the solvent is sublimed from the frozen composition, Producing a partially hydrolyzed gelatin in the form of a net containing a chemical, thereby producing a solid molded product containing a pre-measured unit of chemical and decomposable by water at 5 ° C. within 5 seconds How to. The method of claim 1, wherein the solid molded article is in pharmaceutical dosage form and the chemical is a pharmaceutical substance. The process according to claim 1 or 2, characterized in that the gas phase cooling medium is nitrogen gas. The method of claim 1 or 2, wherein the template is a depression of the sheet of thin film material. 5. The method of claim 4 wherein the wrapper is attached to a thin film bundle around the recess (es) containing the solid molded article.