JPH055065A - New composition containing hydrophilic polymer and hydrophilic substance other than that - Google Patents

Abstract

PURPOSE: To purpose a novel composition which comprises a dispersion medium consisting of a molten body containing a hydrophilic polymer and a dispersed phase containing a hydrophilic substance and can be molded into a product (pharmaceutical capsules, etc.) having dimensional stability and improved dissolution properties.

CONSTITUTION: A composition which comprises (A) a dispersion medium consisting of a molten body containing a hydrophilic polymer (preferably gelatin, etc.) and (B) a dispersed phase containing at least one hydrophilic substance (preferably carboxymethyl cellulose, carboxymethyl starch, etc.) insoluble in A and in which the phase exists in a concentration (the content of the hydrophilic substance is 0.1-4 wt.% based on the weight of the composition) to increase the solubility of a product made from a composition not containing the phase, The hydrophilic polymer is heated at a temperature equal to or above its melting point and glass transition temperature for an enough time to break it structurally, and a substance which functions as a dispersed phase is added before, during, or after the formation of the molten body to obtain an intended composition. The composition is molded into pharmaceutical capsules, etc.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

The present invention relates to a dispersion medium comprising a melt containing a hydrophilic polymer and a dispersed phase containing at least one hydrophilic substance, preferably a water-absorbing substance, which is different therefrom. A composition having improved dissolution properties. Hydrophilic polymer, dispersion medium,
The terms dispersed phase, hydrophilic substance, and hygroscopic substance are defined below.

[0002]

BACKGROUND OF THE INVENTION Many hydrophilic polymers that decompose in the dry state (ie, in the absence of water) without melting even at elevated temperatures produce thermoplastic melts in the presence of limited amounts of water. It is known. An example of such a hydrophilic polymer is gelatin. It is also known that hydrophilic polymers which melt in the dry state with increasing temperature produce a thermoplastic melt at that temperature in the presence of a limited amount of water.

Such hydrophilic polymers are processed at elevated temperatures to form a melt. The method is conveniently carried out in an injection molding machine or extruder. The hydrophilic polymer is fed through a hopper onto a rotating reciprocating screw. The feed material moves to the tip along the screw. During this step, the temperature is raised by an external heater around the outside of the barrel and by the shearing action of the screw. Starting from the feeding section and continuing to the compression section, the fed granules gradually melt. It is then conveyed to the end of the screw through a metering section where homogenization of the melt takes place. The tip melt is then further processed by injection molding, extrusion, or any other known technique for processing thermoplastic melts to provide a shaped article.

This process is described in European Patent Application No. 83,30.
No. 1,643.9 (Publication No. 0,090,600)
It is described in the specification, and the content of the description is included in the present specification by reference.

The preferred hydrophilic polymers of the present invention are natural hydrophilic polymers, especially gelatin. Such gelatins are preferably made from acid- or alkali-treated bone, acid-treated pig leather, or alkali-treated cowhide. Various gelatins of the above type have a composition of 10,000 to 2.0 per mole.
Molar mass range of 0,000 grams (g / mol), or 10,000 to 2,000,000 and 10,000
It has a molar mass range of 20,000 to 20,000,000 g / mol. Such gelatin is known.

However, the other hydrophilic polymers described herein are included in the present invention. Hydrophilic polymers have functional groups in their backbone and / or their side chains that may participate in hydrogen bonding, and have a molar mass of about 10 ³ -10.
It is a polymer of ⁷ g / mol. Such hydrophilic polymers exhibit an inflection point at 0.5 near their water activity point in their water absorption isotherms in the temperature range of about 0 to 200 ° C.

Articles made from such hydrophilic polymer melts are useful in numerous applications. The important characteristics are
The ability of such products to absorb and decompose water.

[0008]

For many purposes,
The rate of degradation must be fast, even for formulation containers. Formulation containers in the form of conventional hard gelatin capsules made by known dip molding methods generally have slightly shorter dissolution times than similar containers made by injection molding methods. The object of the present invention is therefore to reduce the dissolution time of such injection-molded capsules.

[0009]

According to the present invention there is provided a composition of matter which can be formed into a product having substantially dimensional stability and improved dissolution properties, the composition comprising a matrix and a phase. The medium acts as a dispersive medium with respect to the phase, and the phase also acts as a disperse phase with respect to the medium, which phase results in an increase in the solubility of the product compared to the solubility of the product made from the composition without that phase. A composition comprising at least one hydrophilic substance which is present in the composition in a sufficient concentration such that the medium comprises a solidified hydrophilic polymer and the phase is substantially insoluble in the medium forming the hydrophilic polymer. Provided.

The composition is in the form of a powdery mixture of its components, in the form of a melt, or in solidified form obtainable from such a melt, eg granules, pellets,
Or it may be in the form of solid particles such as a powder. These forms of the novel composition are primarily useful in their own right in making the present invention. The pulverulent mixture or solidified form described above is processed into a melt and then the finished product is formed.

The invention especially provides shaped articles such as those obtainable from the composition, which are bottles, sheets, films, packaging materials, pipes, rods, laminated films, large bags, bags, foams. , Granules, powders, and pharmaceutical containers.

The present invention further provides a shaped article as described above when used as a carrier material comprising a component selected from pharmaceutically or veterinarily active compounds.

The present invention is further a composition of matter which can be molded into an article having substantially dimensional stability and improved dissolution properties, the medium acting as a dispersing medium for the phase, the phase also dispersing for the medium. The medium is present in the composition in a concentration sufficient to function as a phase, which causes an increase in the solubility of the product compared to the solubility of the product made from the composition without that phase, and the medium is a solidified hydrophilic Made of a reactive polymer,
A method of making a composition containing at least one hydrophilic substance, the phase of which is substantially insoluble in a medium containing the hydrophilic polymer, the method being sufficient to form a melt of the hydrophilic polymer. Heating the hydrophilic polymer to a temperature above the melting point and glass transition temperature of the hydrophilic polymer for a sufficient period of time to render the substance functioning as the dispersed phase hydrophilic either before, during, or after melt formation. Provided is a method characterized by adding to a polymer.

The present invention further includes injection, molding, blow molding, extrusion, coextrusion, compression molding, vacuum molding, foaming, the composition.
And a method for molding into a shaped article selected from the group consisting of thermoforming.

The dispersed phase is preferably selected from polysaccharides from the group consisting of cellulose, chitin, starch or chitosan, preferably cross-linked and having some of the hydroxyl groups of the constituent anhydroglucose units replaced. Includes fibrous polymers. Alternatively, the dispersed phase can be a polyvinylpyrrolidone polymer.

Such fibrous polymers have been added to gelatin in concentrations of up to 10% in the dip molding process of hard gelatin capsules. However, no increase in the dissolution rate of the capsules so produced was observed when compared to similar capsules produced without the addition of the fibrous polymer described above.

Therefore, although the mixture of the present invention will produce a melt when temperature and pressure are increased in the presence of water,
When present in low concentrations, such fibrous polymers enhance the dissolution properties of the solidified melt.

The present invention will be further clarified by the following description of the embodiments.

The terms "dispersed medium" and "dispersed phase" in the present text are to be interpreted as follows: The composition of the invention is included in the substance and phase contained in the medium. Composed of material. When both the medium and the phase are present in the composition, the medium is not completely immiscible with the phase, i.e. the phase is a requirement of the invention that it is dispersed rather than dissolved in the material containing the dispersion medium. Is. Thus, the phase may contain coarse or fine granules to give a colloidal system, or contain large particles and behave similarly when present in the thermoplastic melt.

The term "hydrophilic substance" in the context of the present invention is a substance which is water-soluble and water-swellable, ie at room temperature in an amount of at least 10 grams per 100 grams of substance, preferably at least 100 grams per 100 grams of substance. By a quantity of 20 grams is meant a substance capable of absorbing water.

The term "hygroscopic substance" in the context of the present invention is interpreted as follows: a water-absorbing substance readily absorbs and / or adsorbs and retains ambient moisture at room temperature, However, it is a substance that does not liquefy due to dissolution of the above substances by absorption, adsorption, and retention of water. Such materials are capable of adsorbing and / or absorbing and / or retaining water at rates up to 1000 times their own weight.

In the text of the present invention, the term "hydrophilic polymer" as defined above refers to the following: substantially water-soluble polymers such as animal gelatin, vegetable gelatin, sunflower protein, soybean. Proteins such as proteins, cottonseed proteins, peanut proteins, rapeseed proteins, acrylated proteins; substantially water-soluble polysaccharides, alkyl starches,
Hydroxyalkyl starches and hydroxyalkylalkyl starches, such as: methyl starch, hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxyethylmethyl starch, hydroxypropylmethyl starch, hydroxybutylmethyl starch; starch esters and hydroxyalkyl starch esters, such as Starch acetate phthalate and hydroxypropylmethyl-starch phthalate; carboxyalkyl starch, carboxyalkylalkyl starch; alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylseal. Loin, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose; cellulose esters and hydroxyalkyl cellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC
P); carboxyalkyl cellulose, carboxyalkyl alkyl cellulose; esters such as carboxymethyl cellulose, and alkali metal salts thereof; water-soluble synthetic polymers such as polyacrylic acid and polyacrylic acid ester, polymethacrylic acid, and polymethacrylic acid ester, Polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polycrotonic acid; polyitaconic acid, polymaleic acid; suitable are furthermore phthalated gelatin, crosslinked gelatin, shellac, succinic acid gelatin, such as tertiary or quaternary amino groups, for example Cation-modified acrylates and methacrylates having dimethylaminoethyl groups, which may optionally be quaternized; as long as they are essentially water-soluble, It includes other similar polymers.

The term "hydrophilic polymer" in the context of the present invention means a polymer which is essentially water-soluble, ie capable of absorbing water at room temperature at a rate of at least 50 grams of water per 100 grams of polymer. ..

If the hydrophilic polymer is not gelatin but only mixes with gelatin, it is sufficient that the hydrophilic polymer is only "water-swellable".
It absorbs at least 10 grams of water per 100 grams of polymer at room temperature. However, such miscible hydrophilic polymers do not produce a separate phase from gelatin. Of course, a mixture of these polymers may be used.

[0025] Gelatins as described above, and gelatins such as those formed in a salt form thereof, and gelatins used for dip molding of hard gelatin capsules are preferred.
When mixing other hydrophilic polymers with gelatin,
These may be mixed in any desired ratio. Preferably gelatin is present in an amount of at least 50% by weight of the total composition, preferably at least 70% by weight and most preferably at least 90% by weight.

When another, essentially water-soluble polymer is incorporated into gelatin, synthetic polymers such as polyacrylic acid, polyacrylic acid esters, polymethacrylic acid,
Polymethacrylic acid ester and polyvinyl alcohol are preferable.

Other hydrophilic polymers, such as those mentioned above, are
Any desired amount, preferably up to 50% by weight, preferably up to 30% by weight, and most preferably the ratio of the other hydrophilic polymer to gelatin of 90 to 97:10, based on the weight of the dry ingredients of the composition. It may optionally be added in an amount of ˜3% by weight.

The water content of such hydrophilic polymer / water compositions is about 1-40% by weight of the total composition, preferably about 5%.
~ 25% by weight. However, in order to make the substance function near its equilibrium water content it gives, 8-20% by weight of the total composition when finally exposed to the atmosphere,
A water content of preferably 10 to 16% by weight should be used for processing. For example, if the gelatin contains only 1-8% water, it is advisable to add some plasticizer to facilitate processing. This is done similarly for other hydrophilic polymers.

For such hydrophilic polymers that are not gelatin, the water content may be generally lower than the water content mentioned above in some cases for cellulose derivatives. However, this is only an experimental optimization that can be easily performed by a person skilled in the art.

The hydrophilic substance of the dispersed phase is above the glass transition temperature of the hydrophilic polymer and preferably absorbs up to 1000 times its own weight in water. The exact amount of water absorbed by the substance will vary depending on its nature, the ionic strength of the aqueous environment in which it is present. For example, the amount of water absorbed is
Generally, it decreases with increasing ionic strength.

The material preferably contains a polymer having a glucose moiety selected from the group consisting of cellulose, chitin, starch and chitosan.

Preferably, at least some of the hydroxyl groups of the anhydroglucose moiety contained in the polymer are substituted, for example by carboxycarboxyalkyl, sulfoalkyl and salts thereof, and dialkylaminoalkyl or quaternary derivatives thereof. .. Such derivatives are, for example, carboxymethyl cellulose, diethylaminoethyl cellulose, triethanolamine cellulose, polyethyleneimine cellulose, and carboxymethyl starch.

In a preferred embodiment, the dispersed phase is included in the above compound which is internally crosslinked. These polymers are preferably substituted to the extent of about 0.5 to 1.2, more preferably to the extent of about 0.7. Preferably, such material is in the form of a thread or fiber,
It has an average twist or fiber length of from about 10 to about 500 μm. The average yarn or fiber length is about 20.
Is preferably about 300 μm, most preferably about 20
It is about 100 μm. The above materials are preferably crosslinked to the extent that they are substantially water insoluble. Preferred crosslinked substances include crosslinked carboxymethyl starch, internally crosslinked carboxymethyl cellulose and salts thereof,
And crosslinked cellulose amines having a tertiary or quaternary amino group.

Internally crosslinked sodium carboxymethyl cellulose is FMC Co under the trade name of Ac-Di-Sol.
Rporation (Philadelphia, US
US-National Formulation US as croscarmellose sodium type A as sold by A).
1 Formulary. The above-mentioned crosslinked carboxymethyl cellulose has an average twisted yarn or fiber length of about 70 to about 80 μm, and has been conventionally used as a disintegrating agent in a concentration of 2 to 6% in tablets and capsules produced by a dry cooling compression method. It was Melt systems, including hydrous hydrophilic polymer melts, which generally use temperatures of 90-180 ° C., as well as elevated pressures, are substantially different from conventional pharmaceutical tablets made at room temperature with substantially dry substances.

Suitable chemically modified starches included in materials such as carboxymethyl starch or sodium starch glycolate are Explotab (Edwar).
dMendell Company Incorpor
aged Carmel, New York), and P
rimojel (Genericchem Corp. L
It is sold under the product name of "Title Falls, New Jersey". The average fiber or yarn length of the modified starch is about 70 μm.

Further, a substance suitable as a hydrophilic substance for the dispersed phase is Fluka Chemie AG (Indust
riesterse 25, CH-9470 Buc
hs, Switzerland) to Avicel P
It is a microcrystalline cellulose sold under the trade name of H-101. The average fiber or yarn length of the above microcrystalline cellulose is about 20 to about 100 μm, depending on the grade used.

Further, a substance suitable as the hydrophilic substance of the dispersed phase is Polyplasmone XL (GAF Co
rp. , New York), or the cross-linked polyvinylpyrrolidone sold under the trade name of Kollidon. The average fiber or yarn length of the polyvinylpyrrolidone above depends on the exact grade used and is generally about 2
It is in the range of 0 to about 250 μm.

Pullulan or pullulan derivatives, which have been rendered substantially insoluble in hydrophilic polymers by crosslinking or acetylation, can be used, for example, as the hydrophilic material of the dispersed phase.

The pullulan or derivative is about 0.5-1.0.
Has been replaced.

The hydrophilic material is present in the thermoplastic melt at a concentration of about 0.1 to about 4% by weight of the weight of the thermoplastic melt. Preferably, the material is present in the thermoplastic melt in a low concentration of about 0.3 to about 2% by weight of the weight of the thermoplastic melt, most preferably about 0.5 of the weight of the thermoplastic melt.
Present in the thermoplastic melt at a concentration of about 1.5%.

The hydrophilic polymer may be mixed with the materials of the dispersed phase, and optionally other additives as described above, in any desired order. For example, the hydrophilic polymer may be mixed with all additives including the material and then heated for structural destruction to form a melt. The granule size of the starting material is not critical and can be processed with standard commercial equipment.

The hydrophilic polymer may be further mixed with optional additives, first with the track-stirring and granulation, and then with the hydrophilic material in the dispersed phase for further processing.

The hydrophilic polymer is preferably combined with the material to produce a free flowing powder useful for continuous processing.
It is mixed with additives as described herein, structurally disrupted and granulated or directly shaped into shaped articles such as drug product containers.

Therefore, the hydrophilic polymer and all additives can be mixed in a conventional mixer and the water content of the hydrophilic polymer is within the above range. This mixture can then be passed through an extruder to produce granules or pellets as a form of shaped article useful for further processing. However, without granulation, the resulting melt is processed directly using the equipment in the next step, including formulation capsules or other containers, blown films, films, sheets, profiles,
It is possible to mold pipes, tubes, foams, or other shaped articles. The sheet can be used for thermoforming.

To obtain a melt of the novel polymer composition of the present invention, it is preferred to heat the extruder screw and barrel for a time sufficient to result in structural failure and melt formation. Depending on the amount and type of additive and the type of hydrophilic polymer used, the temperature is preferably within the range of 50 ° C to 180 ° C, preferably within the range of 80 ° C to 130 ° C. For this melt formation it is preferred to heat the composition in a closed volume. Closed volume is the volume created by the closed action of unmelted feedstock such as occurs in closed containers, or injection molded screws and barrels, or extruders. In this sense, the screw and barrel of an injection molding machine or extruder are
It should be understood to be a closed container. The pressure generated in the closed container corresponds to the vapor pressure of water at the operating temperature,
However, of course, pressure is applied and / or generated as is normally the case with screws and barrels. The preferred application and / or generation of pressure is within the range of pressures that occur in the extruder and is known per se, eg about 150 × 1.
Up to 0 ⁵ N / m ² , preferably about 75 × 10 ⁵ N / m ^2.
Up to most preferably about 5 to about 50 × 10 ⁵ N / m ² . The resulting structurally disrupted hydrophilic polymer composition is granulated and directly mixed with another component by selected mixing and processing techniques to produce a granular mixture of starting materials fed to the screw barrel.

However, the melt obtained in the screw and barrel may be directly processed and injection molded, for example in a suitable mold. That is, if all the necessary ingredients are already present, they are directly further processed into the final product.

With a screw, the granular mixture is generally about 50.
Heated to a temperature in the range of ~ 180 ° C, preferably about 80-130 ° C.

The minimum pressure used to produce the melt is
It corresponds to the water vapor pressure generated at the above temperatures. The process is carried out in a closed volume as described above, ie in the range of pressures that occur in the extruder as described above, or in the range of pressures used for injection molding.

When molding the shaped article by extrusion, the pressure is preferably as described above. When injection molding the melt of the present invention, for example, the normal range of injection pressure used for injection molding is about 100 × 10 ⁵ N / m ² to about 3,000 ×.
10 ⁵ N / m ² , preferably about 400 × 10 ⁵ N / m ^2.
Is about 2,200 × 10 ⁵ N / m ² .

The hydrophilic polymers of the invention used as starting materials can be mixed with different known additives, such as fillers, mold release agents, plasticizers, stabilizers and / or colorants.

Examples of fillers are preferably inorganic fillers in concentrations ranging from about 1 to 50% by weight of the total composition, more preferably from about 2 to about 10% by weight, eg magnesium, aluminum, silicone, titanium. Examples of such oxides include calcium carbonate. Other known fillers may be used.

Examples of lubricants are from about 0.1% of the total composition.
Aluminum, calcium, magnesium, and tin stearate, and magnesium silicate, present in a concentration of about 5% by weight, preferably about 0.1 to about 3% by weight.
Silicone etc. are mentioned.

Examples of plasticizers are about 0.5 of the total composition.
To about 25% by weight, preferably about 0.5 to about 10% by weight, added at a concentration of low molecular weight poly (alkylene oxide) such as poly (ethylene glycol), poly (propylene glycol), poly (ethylene- Propylene glycol); low molecular weight organic plasticizers such as glycerol, pentaerythritol, glycerol monoacetate, diacetate, or triacetate; propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate and the like.

Examples of colorants include known azo dyes, organic or inorganic pigments, or natural colorants. The inorganic pigments are preferably oxides of, for example, iron or titanium, these oxides being known per se, from about 0.001 to about 10% by weight of the total composition, preferably from about 0.5 to about 3. It is added at a concentration in the range of% by weight.

The sum of the water contents in the plasticizer and hydrophilic component is preferably the value indicated for water content, ie
Each does not exceed about 40% by weight of the composition, and most preferably about 30% by weight, which is the most preferred value of water content as described above. Determining the optimum content of water and plasticizer for different hydrophilic polymeric materials will be apparent to those skilled in the art.

The material may further contain stabilizers, such as antioxidants and antibacterial agents. The above substances form a thermoplastic melt in a closed volume, i.e. under controlled water content and pressure, with heating. Such a melt,
For example, injection molding, blow molding, extrusion, and coextrusion (rod, pipe and film extrusion), and compression molding can be used to process known thermoplastics to produce known products. Examples of the molded product include bottles, sheets, films, packaging materials, pipes, rods, laminated films, large bags, bags, foams, pharmaceutical capsules, granules, or powders. The pharmaceutical carrier (capsule) is preferably manufactured by injection molding.

Such mixed substances may also be used as carrier materials for the active substances, active ingredients such as pharmaceutically and / or
Or it may be mixed with agriculturally active compounds such as pesticides or pesticides for the release of these components. The resulting extrudate may be granulated or made into a fine powder.

[0058]

The invention is further described in the following examples. Example 1 100 parts of 240 Bloom commercial gelatin with a water content of 17% by weight, in the form of a dry powder such that free-flowing granules are obtained, 2 parts of Ca-stearate per 100 parts of gelatin, and different concentrations. (See below) of the disperse phase material croscarmellose sodium was mixed vigorously. The concentrations of croscarmellose sodium used were 1 part per 100 parts gelatin, 2 parts per 100 parts gelatin, and 3 parts per 100 parts gelatin.

The granules thus produced are then
18mm screw (L / D ratio: ratio of diameter to length: 2
5. Arburg Allrounder 220-9
0-350) equipped with screw injection molding machine hopper. The processing conditions for this injection molding experiment are shown below: Barrel temperature profile: T _b : 90 ° C./T _m : 125 ° C./T _e : 150 ° C./T
_g : 150 ° C. Screw speed: 160 [rpm] Injection time: 0.2 seconds Cycle time: 5 seconds

The injection pressure is approximately 2000 bar for croscarmellose-free granules, gelatin 100
Vary up to about 2200 bar for granules containing 3 parts croscarmellose per part.

Various gelatin compositions were molded into capsule caps and body parts using a mold with four cavities.

Under these conditions, a good quality gelatin capsule is obtained during continuous processing-the capsule part thus obtained is not pliable and retains its shape during storage.

The capsule container contained paracetamol of 85.4 parts paracetamol, 2.5 parts corn starch, 11.7 parts microcrystalline cellulose (Avicel), and 0.26 parts hydrogenated cottonseed oil. Fill with the same formulation. The container is filled with the paracetamol formulation using a Bosch filling machine.

The dissolution rate of paracetamol from the sample is
It was measured using the standard US Pharmacopeia test procedure for paracetamol capsules. The measurement results are shown in Table 1.

[0065]

[Table 1]

Example 2 100 parts of 240 Bloom commercially available gelatin with a water content of 17% by weight are mixed vigorously with 0.8 part of the dispersed phase material in the form of a dry powder so that free-flowing granules are obtained.

The dispersed phase materials are (a) croscarmellose sodium, (b) crosslinked polyvinylpyrrolidone, (c).
Carboxymethyl cellulose, (d) carboxymethyl starch, and (e) microcrystalline cellulose (Avice)
l).

The granules thus prepared are then
22mm screw (L / D ratio: diameter to length ratio: 2
2. Arburg Allrounder 220-9
0-350) equipped screw-injection machine hopper. The processing conditions for this injection molding experiment are shown below: Barrel temperature profile: _Tb : 90 ° C / _Tm : 155 ° C / _Te : 160 ° C / T
_g : 160 ° C. Screw speed: 250 [rpm] Injection time: 0.2 seconds Injection pressure: 1850 bar Cycle time: 8 seconds

Various gelatin compositions were molded into capsule caps and body parts using a mold with eight cavities. Under these conditions, good gelatin capsules were obtained during continuous processing-the capsule parts thus obtained are not soft and retain their shape during storage.

Very good dissolution properties were obtained in vitro, which are superior to those obtained from capsules prepared without the addition of dispersed phase material.

Example 3 Example 2 was repeated with 240 Bloom of gelatin and a water content of 15% by weight. 100 parts of this gelatin is 0.
85 parts of dispersed phase material and 0.5 parts of magnesium stearate were added and mixed well to obtain free flowing granules. Processing conditions are shown below: Barrel temperature profile: _Tb : 90 ° C / _Tm : 155 ° C / _Te : 160 ° C / T
_g : 160 ° C. Screw speed: 250 [rpm] Injection time: 0.2 seconds Injection pressure: 1800 bar Cycle time: 8 seconds

The same mold as in Example 2 was used. Under these conditions, continuous processing yields good quality gelatin capsules. The capsule body is not flexible and retains its shape during storage. Very good dissolution properties were obtained in vitro.

Example 4 100 parts of 200 gelatin of commercial gelatin at a water content of 12% by weight were mixed with 8 parts of glycerol and 1 part of disperse phase material (as in Example 2) to give various gelatin mixtures. Was fed to an injection molding machine to mold a hard gelatin capsule body part as described in Example 2. The processing conditions are shown below: Barrel temperature profile: _Tb : 90 ° C / _Tm : 120 ° C / _Te : 130 ° C / T
_g : 130 ° C. Screw speed: 250 [rpm] Injection time: 0.2 seconds Injection pressure: 1500 bar Cycle time: 8 seconds

The same mold as in Example 2 was used. Under these conditions, continuous processing resulted in good quality and excellent dissolution characteristics of gelatin capsules.

Example 5 100 parts of 150 Bloom of commercial gelatin at a water content of 12% by weight were mixed with 10 parts of glycerol and 2 parts of dispersed phase material (as in Example 1) and injection molded. ,
Hard gelatin capsule parts were molded as described in Example 3. The processing conditions are shown below: Barrel temperature profile: T _b : 90 ° C./T _m : 110 ° C./T _e : 120 ° C./T
_g : 120 ° C. Screw speed: 250 [rpm] Injection time: 0.2 seconds Injection pressure: 1400 bar Cycle time: 9 seconds

Under these conditions, by continuous processing,
A gelatin capsule of good quality and excellent dissolution properties was obtained.

Example 6 100 parts of 150 Bloom of commercial gelatin with a water content of 12% by weight, at a rate of 5 kg / h, in a twin-screw extruder (W
Arner-Pfleideerer type).
From another port, a 10: 1 mixture of monoglycerin acetate and dispersed phase material was fed to the extruder at a rate of 10 parts per hour. The temperature was kept between 90 ° C and 105 ° C.

The solidified melt was granulated and granules were produced therefrom.

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[Procedure amendment]

[Submission date] October 7, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0013

[Correction method] Change

[Correction content]

The present invention is further a composition of matter which can be molded into an article having substantially dimensional stability and improved dissolution properties, the medium acting as a dispersing medium for the phase, the phase also dispersing for the medium. The medium is present in the composition in a concentration sufficient to function as a phase, which causes an increase in the solubility of the product compared to the solubility of the product made from the composition without that phase, and the medium is a solidified hydrophilic Consisting of surname polymer,
Phase is a process for the preparation of a composition containing at least one hydrophilic material which is substantially insoluble in the medium containing the hydrophilic surname polymer, the method Stora the hydrophilic polymer
Heating the hydrophilic polymer to a temperature above the melting point and glass transition temperature of the hydrophilic polymer for a time sufficient to cause fracture , before, during, or after the melt formation of the substance functioning as the dispersed phase. And a hydrophilic polymer are added to the hydrophilic polymer.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location C08L 5/00 LAW 6770-4J 5/08 LAX 6770-4J 89/00 LSE 6770-4J // C08L 101: 00 (72) Inventor Ebert Thomas Cole Switzerland, Esau, Zweher-4114 Hofstetten, Homershütlerase 36 (72) Inventor Marx Eglie Switzerland, Zweher-5033 Buthus, Im Maitenvejk 1

Claims (1)

Claim: What is claimed is: 1. A composition of matter that can be molded into an article having substantially dimensional stability and improved dissolution properties, the composition comprising a medium and a phase, the medium being related to the phase. Is present in the composition in a concentration sufficient to act as a dispersing medium, the phase also acting as a disperse phase with respect to the medium, which phase results in an increase in the solubility of the product made from the composition without that phase. A composition, wherein the medium comprises a solidified hydrophilic polymer, and the phase comprises at least one hydrophilic substance that is substantially insoluble in the medium containing the hydrophilic polymer. 2. The composition of matter according to claim 1, wherein the hydrophilic substance comprises a hygroscopic substance. 3. A composition according to claim 1, in the form of constituents selected from the group consisting of a powdery mixture of its components, a melt, and a solidified form obtainable from said melt. Composition. 4. A form selected from the group consisting of granules, pellets and powders obtained from the melt.
A composition of the substance according to any one of 1. 5. The hydrophilic polymer comprises the following: animal gelatin, vegetable gelatin, sunflower protein, soy protein,
A substantially water-soluble polymer selected from cottonseed protein, peanut protein, rapeseed protein, acrylated protein; substantially water-soluble polysaccharides, alkyl starches, hydroxyalkyl starches and hydroxyalkylalkyl starches, starch esters and hydroxys. Alkyl starch ester; carboxyalkyl starch, carboxyalkylalkyl starch; alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose, cellulose ester, and hydroxyalkylcellulose ester; carboxyalkylcellulose, carboxyalkylalkylcellulose, and alkali metal salts thereof, Polyacrylic acid and polyacrylic acid ester, polymethacrylic acid, and polymethacrylic acid ester, Vinyl alcohol, polyvinyl acetate phthalate (PVAP), polycrotonic acid; polyitaconic acid, polymaleic acid; phthalated gelatin, crosslinked gelatin, shellac, succinic acid gelatin, cations having a quaternizable tertiary or quaternary amino group. A composition of matter according to any one of claims 1 to 5 selected from the group consisting of: acrylates and methacrylates modified with, but wherein the polymer does not form a dispersed phase. 6. A composition of matter as claimed in any one of claims 1 to 6 in which the hydrophilic polymer is gelatin. 7. The hydrophilic polymer is methyl starch, hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxyethyl methyl starch, hydroxypropyl methyl starch,
Hydroxybutylmethyl starch, starch acetate phthalate, and hydroxypropylmethyl-starch phthalate, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose,
6. A composition of matter according to any one of claims 1 to 5 selected from the group consisting of hydroxypropylmethylcellulose and hydroxybutylmethylcellulose, cellulose acetate phthalate, and hydroxypropylmethylcellulose phthalate. 8. A composition based on the weight of the dry ingredients of the composition of 5
A composition of matter according to any one of claims 1 to 7 further comprising at least one other hydrophilic polymer added to the composition in an amount of up to 0% by weight. 9. A composition according to claim 1, wherein the water content is about 1-40% by weight of the total composition. 10. A composition of matter according to any one of claims 1 to 9 wherein the hydrophilic substance in the dispersed phase has a melting point above the glass transition temperature of the hydrophilic polymer. 11. The hydrophilic material comprises 100 parts by weight of the hydrophilic material.
The composition according to any one of claims 1 to 10, which absorbs up to 0 times the amount of water. 12. The hydrophilic substance is more preferably at a concentration of about 0.1 to about 4% by weight, preferably at a concentration of about 0.1 to about 2% by weight, based on the weight of the composition. At a concentration of about 0.3 to about 2% by weight, most preferably about 0.5.
13. The composition of any one of claims 1-12 present in the composition at a concentration of from about 1.5% by weight. 13. The composition according to claim 1, wherein the hydrophilic substance contains a polysaccharide selected from the group consisting of cellulose, chitin, chitosan and starch. 14. The polysaccharide according to claim 13, wherein the polysaccharide is substituted.
The composition as described. 15. The polysaccharide comprises carboxy-, carboxyalkyl- and salts thereof, sulfoalkyl- and salts thereof,
15. The composition of claims 1-14 substituted with a constituent selected from the group consisting of dialkylaminoalkyl and quaternary derivatives thereof. 16. The composition according to claim 1, wherein the polysaccharide is selected from the group consisting of carboxymethyl cellulose, diethylaminoethyl cellulose, triethanolamine cellulose, polyethyleneimine cellulose and carboxymethyl starch. 17. The polysaccharide is in the form of a thread or a fiber and has a thickness of about 10 to about 500 μm, preferably about 20 to about 30.
17. A composition according to any one of claims 13 to 16 having a length of 0 [mu] m, most preferably about 20 to about 100 [mu] m. 18. The composition according to claim 13, wherein the polysaccharide is crosslinked. 19. A polysaccharide selected from the group consisting of cross-linked carboxymethyl starch and its salts, internally cross-linked carboxymethyl cellulose and its salts, and cellulose amines having a tertiary or quaternary amino group. 19. The composition according to any one of 18. 20. The composition according to claim 13, wherein the polysaccharide is pullulan or a pullulan derivative. 21. The pullulan or derivative is 0.5-1.
21. The composition according to any one of claims 1 to 20, which is substituted to the extent of 2. 22. The composition according to claim 1, wherein the hydrophilic substance comprises internally crosslinked polyvinylpyrrolidone or a salt thereof. 23. A composition of matter according to any one of claims 1 to 22 wherein the composition further comprises additives including extenders, mold release agents, plasticizers, stabilizers and colorants. .. 24. A composition of matter that can be molded into a product having substantially dimensional stability and improved dissolution properties, the composition comprising a medium and a phase, the medium functioning as a dispersing medium with respect to the phase, The phase also acts as a disperse phase with respect to the medium, the phase being present in the composition in a concentration sufficient to result in an increase in the solubility of the product made from the composition without the phase, the medium being solidified hydrophilic. Shaped article obtained from a composition comprising at least one hydrophilic substance, the phase consisting of a hydrophilic polymer and the phase being substantially insoluble in a medium containing the hydrophilic polymer. 25. A product made from the composition of any one of claims 1 to 23. 26. The product of claim 25 in the form of a pharmaceutical capsule. 27. A composition of matter that can be formed into a product having substantially dimensional stability and improved dissolution properties, the composition comprising a medium and a phase, the medium functioning as a dispersing medium with respect to the phase, Also acts as a disperse phase with respect to the medium, the phase being present in the composition in a concentration sufficient to cause an increase in the solubility of the product made from the composition without that phase, the medium being solidified hydrophilic What is claimed is: 1. A method of producing a composition comprising at least one hydrophilic substance, the phase comprising a polymer and the phase being substantially insoluble in a medium containing the hydrophilic polymer, the process comprising the structural destruction of the hydrophilic polymer. Heating the hydrophilic polymer to a temperature above the melting point and glass transition temperature of the hydrophilic polymer for a time sufficient to allow the substance functioning as the dispersed phase to be formed prior to, during, and during melt formation. Or a method of adding to the hydrophilic polymer either later. 28. The method according to any one of claims 1 to 27, wherein the hydrophilic polymer is gelatin. 29. The method of claim 1 under controlled water and pressure conditions.
24. A method of shaping a composition according to any one of claims 2 to 23, wherein the method is selected from the group consisting of injection, molding, blow molding, extrusion, coextrusion, compression molding, vacuum molding, thermoforming, and foaming. How to be done. 30. A product obtained by the method of claim 29.