JPH0774163B2 - Controlled release composition - Google Patents

Description

Description: FIELD OF THE INVENTION This invention relates to compositions that provide controlled release of an active agent into an aqueous phase.

Background of the Invention It is known to release active substances, for example pharmaceutically active powders, by embedding them in a matrix of insoluble substances in which the active substance diffuses slowly. The sustained release of the active substance contained in the tablet core is achieved by applying to this core a semipermeable coating through which water and the dissolved active substance diffuse, or an insoluble coating having through holes through which the active substance is released. Done by. Further, the sustained release of the active substance is carried out by microcapsulating the particles of the active substance in a layer of one or more films of various types such as a type that mediates diffusion of the active substance or releases the active substance into the intestine. It is achieved by

These conventional methods of sustained release of active substance have several drawbacks. That is, it is difficult to maintain a constant concentration of the active substance, for example, a constant plasma concentration of the pharmaceutically active substance throughout the entire period when the dosage form is present in the body. This is especially a problem for drugs with a short half-life in the body. In addition, water can penetrate through the diffusion coating, causing hydrolysis of labile actives in an aqueous environment.

The aim of the present invention is to overcome these disadvantages by providing a composition which tightly controls the release of the active substance and prevents the active substance from being decomposed by hydrolysis by release.

SUMMARY OF THE INVENTION Accordingly, in one aspect, the invention provides a composition for controlled release of an active substance in an aqueous phase by the erosion of one or more surface layers of the composition at a substantially constant rate. The composition is based on a matrix of a substantially water-soluble crystalline polymer or a mixture of substantially water-soluble crystalline polymers, the crystalline polymer and a surfactant. One surfactant or a mixture of surfactants dispersed in the crystalline polymer phase in an amount of 0 to 50% by weight, provided that the surfactant is compatible with the crystalline polymer phase. A compound or compounds having at least one region and at least one other region that is substantially oil-repellent and having a melting point lower than that of the crystalline polymer), and Uniformly dispersed in crystalline polymer layer And / or consisting of at least one active agent dispersed in a surfactant and / or located in a geometrically well-defined area within the composition, and optionally a filler; And / or the active substance reduces the water affinity between the particles and cracks in the crystalline polymer matrix and the regions of the crystalline polymer matrix itself, thus substantially diffusing water at the interface between the polymer crystals. , So that the erosion is predominantly carried out by the dissolving action of the aqueous medium on one or more surface layers of the composition exposed to the aqueous medium.

The combination of the matrix and the active substance and / or the surfactant is used in the present invention in order to prevent the active substance present in the matrix from being decomposed by the action of water when the active substance is easily hydrolyzed. Of the composition of the present invention (for example, in the gastrointestinal tract including rectum, intravaginal or subcutaneous) or through a catheter into a body cavity (for example, bladder, gallbladder, uterus, central nervous system cavity, infection / malignant / recess after surgery, etc. 3.) It must be substantially impermeable to aqueous phase fluids such as body fluids present at the site of introduction. Encapsulation of the active agent in a matrix in which diffusion of water is substantially eliminated confers stability to the composition and, as a result, even when the composition is exposed to a fluid such as body fluid for a predetermined amount of time. The active substance remains active. If the fluid acts only on the surface of a matrix of this kind, the active substance embedded in the matrix is only exposed to the fluid in question at or shortly before its release from the matrix. Therefore, a substantially water-impermeable type of matrix is one in which the composition is such that the release proceeds progressively from one or more surface layers of the matrix exposed to the fluid in question, such that the composition has an aqueous phase (eg, Guarantees the stability of the active substance in the matrix and guarantees a controlled and reproducible release rate of the active substance from the matrix until the active substance is released throughout its lifetime in the body cavity) To do.

The rate at which the active substance is released from the matrix is a predetermined rate, ie a rate that is controllable over some time. The release rate required for each particular case depends inter alia on the amount of active substance to be released in order to exhibit the desired effect and on the total dose of active substance contained in the matrix. Therefore, the substances that make up the matrix and the distribution of the active substance within the matrix are selected by one or more of these criteria ensuring that the active substance is released at the desired level.

The composition of the invention has the advantage that the dose of the active substance contained in the matrix can be measured, so that a suitable constant or pulsatile dose of the active substance is It can be obtained in the aqueous phase throughout the whole period in which it is present. In other words, even if the active substance in the matrix is unstable in the aqueous environment due to the nature of the matrix structure, that is, its water impermeability, the active substance may be hydrolyzed by diffusion of water into the matrix. It is prevented from being decomposed.

Due to the controlled release of the active substance obtainable from the composition according to the invention, corresponding to the dose required for the treatment of the problem,
A substantially constant release rate or controlled pulsatile release of the active substance can be achieved over a certain period of time, so that, for example, at regular intervals many times a day,
It is not necessary to adhere to the strict dosing regimen in which the drug needs to be administered. In addition, two or more active agents can be included in the compositions of the present invention and configured to release at varying concentrations and / or intervals so that the patient can easily follow a given regimen. .

Another advantage of the compositions of the invention over other known controlled release compositions is that they can be produced in a relatively simple and inexpensive way, for example by the extrusion method, which is described below. Detailed description. In addition, the compositions of this invention may incorporate high concentrations of active agent, relative to the size of the composition. The above is a particularly great advantage, especially when used for the release of pharmaceutically active substances, since the compositions according to the invention can release the required amount of active substance without being unnecessarily large. Moreover, poorly soluble or insoluble substances can be readily incorporated into the compositions of this invention. This is because these substances are compatible with the lipophilic region of surfactants. Thus, the compositions of this invention can be used, for example, to release poorly soluble or insoluble pharmaceutical powders that are difficult to administer by external methods.

Besides containing a water-soluble crystalline polymer or a mixture of such polymers, the matrix is capable of at least partially approaching the water-insoluble substance and the active substance and the aqueous phase fluid and said fluid. May also be included with a hydrophilic substance that swells in the presence of, so that the matrix in the vicinity of the hydrophilic substance disintegrates locally to release the active substance.

In another embodiment, the present invention is a composition for controlled release of an active substance into an aqueous phase, which is made of room temperature vulcanized rubber (RTV rubber), in which particles of superabsorbent polymer are substantially uniform. A matrix that is distributed in the matrix and is substantially in the vicinity of the surface of the composition, and that is substantially evenly distributed within the matrix and / or is located in a geometrically well-defined region in the matrix. Consisting of at least one active substance, the liquid of the aqueous phase is able to diffuse into the matrix at a limited rate, so that the particles of the superabsorbent polymer swell and the matrix near the swollen particles is locally destroyed. And as a result, according to the distribution of the active substance in the matrix,
It relates to compositions in which the active substance is released in a specifically controlled manner.

DETAILED DISCLOSURE OF THE INVENTION In a first embodiment of this invention, ie, where the matrix of the composition comprises a substantially water-soluble crystalline polymer or a mixture of substantially water-soluble crystalline polymers. The surfactant is generally dispersed in the crystalline polymer layer.

The surfactant is at least 1 compatible with the crystalline polymer phase.
One compound or a plurality of compounds having one region and at least one other region that is substantially lipophilic. The term "compatible" as used in the specification of this invention means that the surfactant can be emulsified in the molten polymer as described below. Surfactants have regions of substantial hydrophilicity that act in part as a repair medium and give the surfactant an affinity for the crystalline polymer phase, resulting in particles of the crystalline polymer matrix. The substantially lipophilic region, which fills the interstices and the regions of the fissures, and partially as a surfactant, reduces the water affinity of the interfacial particles and fissures in the crystal structure, resulting in a polymer Substantially eliminates the diffusion of water at the interface between crystals.

The cracks and particles in the crystalline polymer matrix are:
Crystals are the result of the process by which they are formed. During the crystallization process, the matrix tends to shrink, forming cracks and imperfect regions between the crystal grains. In order to retain its function as a repair medium, the surfactant must flow after the matrix polymeric material solidifies to form crystals. Therefore, the melting point of the surfactant must be lower than the melting point of the crystalline polymer phase.

In order for the surfactant to function properly as a repair medium for matrix crevices and particles, the surfactant must also be substantially evenly distributed in the molten polymer before the polymer crystallizes. It is necessary to be able to do it. The surfactant must therefore be emulsifiable in the melt polymer.

It has been found that a substantially hydrophobic active agent tends to reduce the erosion rate of the composition. Substantially hydrophilic or water-soluble active substances have been shown to have the opposite effect. That is, this material tends to accelerate the erosion of the matrix. Furthermore, it has been found that when the composition is prepared without active substance, the composition tends to erode at a relatively fast rate.

The degree of dispersion of the surfactant in the matrix appears to be important for the erosion rate of the matrix, the more uniform the dispersion, the slower the erosion rate. Thus, a substantially hydrophobic active agent tends to result in a more uniform dispersion of the surfactant, thus reducing the erosion rate of the matrix,
On the other hand, non-hydrophobic active substances are considered to have the opposite effect.

If the composition is made of an active substance that is not substantially hydrophobic, or if the content of the active substance in the composition is relatively low, it therefore improves the dispersion of the surfactant and reduces the erosion rate of the matrix. To this end, it is desirable to add one or more fillers. It is considered that the addition of the filler has the function of increasing the viscosity of the mixture, so that the surfactant can be more uniformly dispersed in the matrix. Examples of suitable fillers are dextrins, sucralfates, calcium hydroxyl-apatite, calcium phosphates and fatty acid salts such as magnesium stearate. Fillers, which are the combination of this with the active agent, generally comprise up to about 60% by weight of the composition.
It may be added in an amount such that it constitutes up to 50% by weight.

Surfactants generally have 12 to 24 carbon atoms, generally 12 to 20 carbon chains, such as one or more fatty acid esters and / or fatty acid ethers, for example palmitic or stearic acid esters and / or ethers. It is a nonionic emulsifier comprising a fatty acid ester and / or a fatty acid ether. Representative surfactants include esters or ethers of polyglycols, esters or ethers of polyethylene glycols, polyhydroxyesters or polyhydroxyethers and / or sugar esters or ethers such as sorbita esters or ethers. Suitable surfactants have an HLB (hydrophile-lipophile ratio) value of about 4 to about 16. Furthermore, as the surfactant, an emulsifier which is acceptable for use in products for human or animal ingestion, that is, pharmaceuticals and / or foods is preferable. A preferred surfactant is polyethylene glycol monostearate, especially polyethylene glycol 400 monostearate. Esters of tartaric acid, citric acid and lactic acid of mono- and di-glycerides and fatty acid esters of glycerol are also available as surfactants.

It may be preferable to incorporate a mixture of surfactants into the matrix in order to improve the dispersion of the main surfactant into the matrix and reduce the erosion rate.

In some cases, the active substance itself can function as a surfactant. That is, the active agent has at least one region that is compatible with the crystalline polymer phase and at least one other region that is substantially lipophilic, so that only the active substance is within the crystalline polymer phase. Can be dispersed substantially uniformly and the diffusion of water into the matrix is substantially eliminated. In this case, little or no surfactant is needed, since the role of the surfactant, ie the function as repair medium and surfactant, is partially or completely fulfilled by the active substance itself. Therefore,
If the active substance itself has the properties of a nonionic emulsifier, the surfactant may not be present in the composition or may be present in the composition in an amount of, for example, about 0 to 2% by weight, based on the matrix. May be.

If the active material does not have the properties of a surfactant, then the surfactant is present in the composition in an amount of about 2-50% by weight, based on the crystalline polymer and surfactant, such as about 5-50% by weight. %, Generally about 10-40% by weight, more usually about 15-35% by weight, for example about 20-30% by weight. However, when the active substance has the properties of a surfactant as described above,
The surfactant content may be less than 2%. On the other hand, depending on the properties of the surfactant, the active substance and the crystalline polymer, and the desired release characteristics of the composition, a maximum surfactant content of about 50% ensures the necessary repair and surfactant effects. Can be satisfied. If the surfactant content exceeds about 50%, there is a risk of phase inversion,
Therefore, the surfactant may become a continuous phase.

The crystalline polymer matrix is generally composed of polyglycol, for example in the form of homopolymers and / or copolymers. Preferred polymers are polyethyl glycols or block copolymers of ethylene oxide and propylene oxide. Suitable polyethylene glycols for use in the crystalline polymer matrix have a molecular weight of about 2,000 to about 500,000 daltons, generally about
5,000 to about 100,000 daltons, more commonly about 10,000 to
It is about 50,000 daltons, especially about 20,000 to about 35,000 daltons. Preferred polyethylene glycols have a molecular weight of about
It is for 35,000 Daltons. A typical block copolymer may contain up to about 30% by weight of polypropylene oxide based blocks and has a molecular weight of about 5,00.
Over 0 Dalton, generally about 5,000 to about 30,000 Dalton,
More generally, it is about 8,000 to about 15,000 daltons.

The crystalline polymer matrix must have a melting point above the temperature of the aqueous medium in which the composition of this invention is used. Therefore, the polymer used for the matrix has a melting point of about 20-depending on how the composition is used.
120 ° C, generally about 30-100 ° C, more typically about 40-80
℃. In particular, when the composition of the present invention is used to release a drug used in humans or livestock, a matrix having a melting point of about 40-80 ° C is suitable.

Active substances released by the composition of the present invention include human or veterinary drugs, enhancers such as vitamins, disinfectants, deodorants,
Alternatively, it may be another substance that is continuously administered to the aqueous environment.

The compositions of this invention are particularly suitable for the release of pharmaceutically active substances, especially active substances which are pharmaceutically active powders.
The pharmaceutically active substance (s) contained in the composition of the present invention is selected from a number of therapeutic categories, in particular administered orally, rectally, vaginally or subcutaneously, Alternatively, it is selected from substances that are advantageous to be administered to body cavities (eg bladder, gallbladder, uterus, central nervous system depression, infected / malignant / postoperative depression, etc.). Examples of such substances are antimicrobial agents, analgesics, anti-inflammatory agents, anti-anti-stimulants, aggregation-altering agents, diuretics, sympathomimetics, anorectic agents, gastrointestinal agents such as antacids, antiparasitic agents. , Antidepressants,
Antihypertensive, anticholinergic, stimulant, antihormone, central nervous system stimulant, respiratory stimulant, drug antagonist,
Lipid regulators, uric acid excretion enhancers, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, parasympathomimetics. , Anticonvulsants, antihistamines, β-blockers,
Drugs such as laxatives, antiarrhythmic agents, contrast agents, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antiviral agents and anticancer agents with anticancer properties or cytostatics, or mixtures thereof. is there. Other suitable active substances may be selected from contraceptives and vitamins and trace and macroelements.

The composition of the invention further comprises the release of hormones such as growth hormone; enzymes such as lipases, proteases, carbohydrases, amylases, lactoferrin, lactoperoxidase, lysozyme, nanoparticles, and polypeptides such as antibiotics. Suitable for. The compositions of this invention can also be used to release live, attenuated or dead microorganisms.
These microorganisms include bacteria such as gastrointestinal bacteria such as streptococci such as S. faecium, Bacillus such as B. licheniformis and B. Subtilis. Genus species bacteria, lactobacilli, Aspergillus species bacteria;
Bifidus agonists; or viruses such as resident viruses as vaccines, enteroviruses, bacteriophages; and fungi such as baker's yeast, Saccharomyces cerevisiae and incomplete fungi. The composition of the invention can also be used for the release of active substances in specific carriers such as liposomes, cyclodextrins, nanoparticles, micelles and fats.

One application for which the compositions of this invention are suitable is for vaginal release of antimicrobial agents. Examples of these agents are antifungal agents, for example imidazole antifungal agents such as clotrimazole, econazole, ketoconazole and miconazole; polyene antifungal antibiotics such as nystatin; and antigens such as metronidazole and ornidazole. It is an insect remedy.

Suitable pharmaceutically active powders to be administered by the compositions of this invention have a particle size of from about 0.1 μm to about 500 μm, generally from about 0.5 μm to about 300 μm, and more typically about 1 μm.
μm to about 200 μm, especially about 5 μm to about 100 μm.

The active substance may comprise up to about 60% by weight of the composition, generally about
Present in amounts up to 50% by weight. An active material content of about 60% is considered to be the maximum content of crystalline polymer matrix and surfactant which can be included in the composition in sufficient quantity. On the other hand, the active substance may be included in the composition in smaller amounts, depending on the nature and strength of the active substance in question.

As mentioned above, the presence of surfactants and / or actives in the crystalline polymer matrix reduces the water affinity between the particles in the matrix and in the region of the fissures, thus leading to the interface between the polymer crystals. Of water is substantially eliminated so that the erosion is predominantly due to the dissolution action of the aqueous medium on the surface layer or layers of the composition exposed to the medium. The diffusion of water into the composition is thus substantially limited to the surface layer of the matrix, so that the matrix erodes at a substantially constant and pH independent rate. The result is a substantially zero order release of the active agent, which term refers to the release rate of the active agent when the active agent is substantially evenly distributed within the matrix. It is substantially constant over time. When the active substance is located in a well-defined geometrically well-defined area in the matrix, the pulsatile release of the active ingredient is tightly controlled due to the constant erosion rate of the matrix. To be done.

The composition geometry is important in obtaining the controlled zero-order or pulsatile release described above. Therefore,
In a preferred embodiment of this invention, the composition of this invention has a geometry that allows a substantially constant surface layer to be exposed while the matrix is eroded.
Thus, the composition of the present invention may have the form of a cylindrical rod with a coating that is substantially insoluble in and impermeable to fluids such as body fluids during the targeted release period, The coating has openings at one or both ends. Polymers useful as coatings are preferably those that can be processed by extrusion, in the form of solutions or dispersions. Most preferred are those available in food grade or pharmaceutical grade quality. Examples of such polymers are cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, Teflon, polylactic acid or Polyglycolic acid and its copolymers, such as ethylene-vinyl acetate (EV
A), styrene-butadiene-styrene (SBS) and styrene-isoprene-styrene (SIS).

Further, the coating may be composed of any of the matrix materials listed above, in which case the material is in a form that erodes at a significantly slower rate than the outer matrix. Thus, the coating may consist of a matrix of one or more substantially water-soluble crystalline polymers and a surfactant, the coating comprising:
A coating that erodes in the aqueous phase at a significantly slower rate than the matrix material containing the active substance, so that a substantially constant area of the matrix containing the active substance is exposed during erosion of the composition, and The coating is substantially eroded when the matrix containing the active substance is eroded. Such a coating is designed so that its longitudinal erosion rate is about the same as the longitudinal erosion rate of the matrix, so that the matrix and coating are longitudinally centered on the composition. Are eroded at substantially the same rate toward. Thus, when the matrix is completely eroded by the aqueous medium, the coating is also substantially completely eroded. A composition with such a coating has the obvious advantage of being completely biodegradable when the active substance is released. Such coatings are commonly made with polyethylene glycol, such as polyethylene glycol 400.
It is a combination of monostearate and a mixture of other surfactants and may contain a filler. The content of the mixture of surfactant and filler in the coating is determined for each particular case by characteristic values such as the erosion rate and the size of the matrix containing the active substance.

Moreover, the coating is one that disintegrates or breaks after the matrix has eroded. This type of coating remains unmodified as long as it is supported by the matrix containing the active substance, but disintegrates or crumbles as a result of the loss of its ability to remain unmodified after the matrix has been eroded, resulting in matrix degradation. Are completely eroded and do not remain, for example in the human or animal body, for a significant period of time after the active substance has been released.

The composition in the form of a cylindrical rod may also be produced without coating. In this case, near-zero-order or near-zero-order release of the active substance is obtained, for example, when the active substance is located substantially outside the composition.

Alternatively, the composition of the invention may be hollow cylindrical or hollow hemispherical. The term "cylindrical rod" or "hollow cylinder" as used in this invention refers not only to geometries having a substantially circular cross section, but also to other substantially cylindrical, eg somewhat flat, cross sections. With, eg having a substantially oval or elliptical cross section. In addition, other geometrical forms, such as flat, substantially rectangular or elliptical, which result in a near zero order release of the active substance which is distributed substantially uniformly in the composition, since it only reduces the surface layer of the composition to a relatively small extent. Tablet- or plate-shaped compositions having a shaped cross section are also utilized.

It will be appreciated by those skilled in the art that certain finish forms of the compositions of this invention will include certain minor modifications to facilitate the use of the compositions in question. For example, a cylindrical rod-shaped composition that releases a medicinal powder may have rounded ends to avoid injury or discomfort that may occur when it is introduced into the body. Further, the hollow cylindrical composition may be optionally filled with a readily soluble substance such as a low molecular weight polyethylene glycol, for example, a polyethylene glycol having a molecular weight of about 1,500 to 6,000.

As mentioned above, the active substance can be dispersed substantially uniformly in the crystalline polymer matrix, in which case
A substantially zero order release of the active substance is achieved. Alternatively, pulsatile release of active can be obtained with the compositions of this invention consisting of alternating layers. Thus, pulsatile release has a layer having the above-mentioned cylindrical rod shape, an active layer optionally comprising a crystalline polymer matrix and a surfactant, the active ingredient optionally dispersed substantially uniformly in the matrix. Achieved in a composition comprised of alternating substantially transverse layers of components, the active ingredients optionally being substantially uniformly dispersed in a crystalline polymer and a surfactant. It Similarly, a hollow cylindrical composition comprises a layer of a crystalline polymer matrix and a surfactant, optionally containing the active ingredient substantially uniformly dispersed in the matrix, and a layer of the active ingredient. It consists of alternating layers of layers in which the active ingredient is optionally substantially uniformly dispersed in the crystalline polymer and the surfactant. In a composition of alternating layers, the alternating layers may each contain two or more different active substances.

These two release patterns (ie, zero-order and pulsatile release patterns) are such that a uniform release of one active agent (eg, at a fairly low dose level) results in a single release of the same or another active agent (eg, a high dose). May be combined in an alternating manner (at level).

In another embodiment of this invention, a composition comprising a matrix of room temperature vulcanized rubber (RTV rubber) in which particles of superabsorbent polymer are substantially evenly distributed; The particles are substantially in the vicinity of the surface of the composition so that the liquid of the aqueous phase can diffuse into the matrix at a limited rate, causing the superabsorbent polymer particles to swell, The controlled release of the active substance into the aqueous phase, as described above, is achieved by the composition in which the matrix in the vicinity of the swollen particles is locally destroyed and the active substance is released. Also, the diffusion of water into the composition of this aspect of the invention is substantially limited to the surface layer, so that the active agent is released in a manner that is specifically controlled by its distribution in the matrix.

The RTV rubbers used are generally composed of one or more component RTV silicone elastomers based on polymethylsiloxane. The matrix of RTV rubber further contains a catalyst and optionally a crosslinker. A suitable catalyst is about 0.01-0.1% of stannous octoate or a platinum-divinyltetramethyldisiloxane complex containing about 3-3.5% platinum. Suitable crosslinkers include 0-40% 1,3
Divinyltetramethyldisiloxane, 1,1,3,3-tetramethyldisiloxane or 1,3,5,7-tetramethylcyclotetrasiloxane.

Superabsorbent polymer particles are capable of remaining in a semi-solid state upon absorption of water or other liquid and have at least about 10 times their own weight of water, generally at least about 100 of their own weight.
It is a particle that can absorb twice as much water, especially at least about 200 times its own weight in water. Further, the superabsorbent polymer particles,
It is capable of remaining in a semi-solid state when absorbing body fluids and having at least about 5 times its own body weight, generally at least about 20 times its own body weight, especially at least about 40 its own body weight.
It can absorb twice as much body fluid. Representative superabsorbent polymers suitable for use in this aspect of the invention are polyacrylic acid, modified polyacrylic acid, carboxymethylcellulose, modified carboxymethylcellulose and crosslinked polyvinylpyrrolidone.

The extent of localized disruption is determined, inter alia, by the desired release rate of the active substance, but in any case to ensure that the disintegration proceeds at a substantially uniform rate from the surface inward of the matrix. In addition, it must be sufficient to allow the other superabsorbent polymer particles to approach the fluid in question. The amount of superabsorbent polymer contained in the matrix will vary depending on the swelling power of the particular superabsorbent polymer selected and the manner in which the polymer is arranged in the matrix, but a suitable amount is To about 5 to 75% by weight, generally about 10 to 50% by weight, and more typically about 20 to 40% by weight.

The active substance contained in the above aspects of the invention may be any of the above. Ie human or veterinary drugs,
Enhancers such as vitamins, disinfectants, deodorants or other substances that are continuously administered to an aqueous environment, and pharmaceutically active powders, such as those of the types and particle sizes described above. The content of active substance is up to about 60% by weight of the composition, generally up to about 50% by weight, but it may be lower.

Also, the compositions of the above aspects of this invention must have a geometrical configuration such that a substantially constant surface area can be exposed during erosion of the matrix, so that
The desired zero-order or pulsatile release of the active substance is achieved by the distribution of the active substance in this composition. Therefore, the particular geometric form may be any of the forms described above.

The active substance in the above aspect of the invention is dispersed in the matrix substantially uniformly, in which case a substantially zero order release of the active substance is achieved. The composition of this embodiment may also have alternating layers, in which case pulsatile release of the active substance is achieved. Pulsatile release thus has the above-mentioned cylindrical rod shape, a layer of matrix, optionally containing the active ingredient substantially uniformly dispersed in the matrix, and a layer of active ingredient, the active ingredient of which is optionally matrix. It can be achieved with the composition of this aspect of the invention composed of alternating substantially transverse layers, consisting of layers that are substantially uniformly distributed in the material. Similarly, a hollow-cylindrical composition comprises a layer of a matrix, optionally containing an active substance substantially evenly dispersed in the matrix, and an active substance, the active substance optionally in a matrix material. It is composed of alternating layers located in the longitudinal direction, with the layers being substantially evenly distributed.

As mentioned above, each of the alternating layers may contain two or more different active substances. Also, two release patterns (ie, zero order and pulsation and release pattern) may be combined in the composition of this aspect of the invention such that a uniform release of one active agent (eg, fairly low). Dose level) is alternated with a single release of the same or another active agent (eg at high dose level).

The composition of any aspect of this invention may further be used for the manufacture of multi-unit pharmaceutical formulations, for example in the form of capsules or tablets. A multi-unit pharmaceutical formulation is a formulation made up of a number of individual units, which are generally available when the capsule or tablet formulation disintegrates in the stomach of a human or animal digesting it. It is contained in such a form. Thus, in this case, at least some of the individual units in the multi-unit pharmaceutical formulation described above are comprised of the composition of the invention, and the individual units are sized to be incorporated into the formulation.

The compositions according to the invention may, depending on the desired embodiment and the substance used in the composition in question, be a method known per se in the pharmaceutical industry, or the various methods used, for example, for the production of polymer-based materials. Can be manufactured in. As mentioned above, one advantage of the composition of the present invention is that it can be produced in a relatively simple and inexpensive manner.

Thus, uncoated compositions can be produced, for example, by extrusion, injection or compression molding processes,
Coated compositions, on the other hand, can be produced, for example, by coextruding the coating with the matrix and active substance, injection coating after injection molding or solvent coating by spraying or dipping after extrusion or injection molding. it can.

To produce a composition having a crystalline polymer matrix, the polymer and surfactant are generally mixed with heating and stirring at a temperature sufficient to melt the polymer,
A substantially homogeneous mixture is obtained. If the active substance is contained in the matrix, it is added to the molten mixture of polymer and surfactant or to the mixture before heating. The resulting molten mixture is then extruded or injection molded, for example, as described below. In order to produce a composition which pulsatile release of the active substance,
The active substance may conveniently be included in the matrix material and the mixture of active substance and matrix material may be extruded or injection molded to form layers alternating with layers of matrix without active substance.

To produce a composition containing a matrix of RTV rubber, the components of the matrix, namely the RTV rubber substance, the superabsorbent polymer and the catalyst promoter and / or crosslinker components, are generally mixed with stirring at room temperature. The resulting mixture is then extruded or injection molded, for example as described below. The active substances may be added to the mixture, for example prior to extrusion or injection molding, or may be extruded or injection molded separately, depending on the desired properties of the composition.

For example, to produce a cylindrical rod-shaped composition, a matrix material containing the active substance is injected and molded into a prefabricated tube. Alternatively, the cylindrical rod-shaped composition can be prepared by injecting alternating layers of matrix material and active substance, respectively, into the tube. Cylindrical rod-shaped compositions may also be prepared, for example, by extruding a matrix material with an active substance dispersed therein and then dip-coating, or a) co-imposing the matrix material with the active substance dispersed therein and b) the coating. It can also be produced by extrusion.

Cylindrical rod-shaped compositions can also be prepared by injection-molding processes, including coatings and active substance-containing matrices, including two-component or multi-component injection molding processes. The injection molding method is particularly suitable for compositions with an erodible coating, or a coating that disintegrates or breaks when the matrix is eroded, but is also applicable to other compositions. A cylinder, which generally functions as a coating, is produced in a first step, for example around an iron core, and then in a second or multi-step process, the iron core is removed, after which the matrix is produced by injecting a matrix material. This method is advantageous in that it is simple and suitable for mass production.

The hollow cylindrical composition can be produced, for example, by an extrusion method, a compression molding method or an injection molding method. The hollow hemispherical composition can be produced, for example, by a compression molding method or an injection molding method.

Manufacturing methods, including co-extrusion (for making cylindrical rod-shaped compositions) and extrusion (for making hollow-cylindrical compositions) are simple and inexpensive methods for mass production of the compositions of this invention. It is particularly advantageous in this respect. The rod or tube made by coextrusion or extrusion is then cut into appropriately sized small segments. The composition is then finished, for example, by rolling the ends of individual cylindrical rods or hollow cylinders.

The molten matrix material of the composition, which primarily uses crystalline polymers, generally sets significantly faster than the matrix of the composition based on RTV rubber. Therefore, methods involving extrusion methods are often more suitable for compositions consisting of a crystalline polymer matrix, while compositions consisting of a matrix of RTV rubber are commonly used, for example in prefabricated tubes. It is often more appropriate to fabricate by injecting.

The amount, size and particular form of the active substance of the composition according to the invention will, of course, vary with the nature of the active substance in question and the intended use of the composition. Therefore, when the composition of the present invention is a composition that releases a pharmaceutically active powder,
The particular dosage administered to a human or animal will depend on such factors as the condition and age of the patient and the particular condition to be treated.

The present invention will now be described more fully hereinafter with reference to the accompanying drawings.

FIG. 1 shows a cross-sectional side view of a coated cylindrical rod-shaped composition with a constant release of active substance. This composition consists of an active substance which is distributed substantially uniformly in a matrix 2 and is coated with a coating 1 which is open at one end. Coating 1 is used during the targeted release period
It is substantially insoluble and impermeable to fluids such as body fluids. Therefore, the matrix 2 is gradually eroded from the open end by the action of the aqueous medium in which the composition is used, so that the surface area of the matrix 2 exposed to the aqueous phase remains substantially constant over time. Yes, the active substance is released at a constant and tightly controlled rate.

FIG. 2 shows the same composition as shown in FIG. 1 except that the composition is open at both ends, the matrix 2 being eroded from each open end of 2 towards the center.

FIG. 3 shows a cross-sectional side view of a coated cylindrical rod-shaped composition which pulsatile release of the active substance. The composition consists of matrix layers 2 and active substance layers 3 alternating with each other, covered with a coating 1 and open at one end. The coating 1 is substantially insoluble in and impermeable to fluids such as body fluids during the targeted release period. The matrix layer 2 is thus gradually eroded from the open end by the action of the aqueous medium in which the composition is used, and the active substance 3 is released all at once in a controlled manner as each successive layer 2 of the matrix is eroded. To be done. Also, such a composition may be provided with openings at both ends.

FIG. 4 shows a cross-sectional side view of a composition that releases two active agents. Several transverse layers 3 containing a high concentration of active substance are arranged in a matrix 2 in which the other active substances are evenly distributed in a low concentration, the composition being used during the targeted release period of body fluids. Is coated with a coating 1 which is substantially insoluble in such fluids and impermeable to these fluids.
The active substance contained in the matrix 2 is released at a substantially uniform rate and the active substance contained in the layer 3 is released all at once.

FIG. 5 shows a hollow cylindrical composition. The composition has the active substance substantially evenly distributed in the matrix. Since the matrix is eroded from both the inner surface 1 and the outer surface 2 of the hollow cylinder, the surface area exposed to the aqueous phase fluid remains substantially constant over time,
As a result, a substantially zero order release of the active substance is achieved.

FIG. 6 shows a hollow hemispherical composition, the active substance of which is
It is distributed substantially uniformly in the matrix. Since the matrix is eroded from both the inner surface 1 and the outer surface 2 of the hollow hemisphere, the surface area of the aqueous phase exposed to the fluid remains substantially constant over time, so that the active substance A substantially zero order emission of is achieved.

FIG. 7 shows the composition in tablet form, the active substance being distributed substantially uniformly in the matrix. The matrix is
The surface area of the aqueous phase exposed to the fluid remains substantially constant over time as it erodes primarily from two relatively large flat surfaces, resulting in a substantially zero order of the active agent. Emission of is achieved.

FIG. 8 shows a cross-sectional side view of a cylindrical rod-shaped composition having a coating 2 which erodes at a substantially lower rate than the matrix 1 containing the active substance. When present in the fluid for a period of time, the matrix 1 erodes from each end to 4 while the relatively slowly eroding coating 2 erodes to 3.

The present invention is further disclosed in the following examples, which are not intended to limit the present invention.

Example 1 Patent Blue was mixed thoroughly with 20,000 molten polyethylene glycol (PEG) matrix material.
The final product matrix contained 25% patent blue and 75% PEG20,000. While the temperature is high,
The matrix was extruded with a syringe into a premade silicone tube with an inner diameter of 4 mm and then allowed to cool. The tube is cut into segments about 2 cm in length, leaving openings at either end of the dosage form for active substance release. Synthetic urine (1.94% urea, 0.8% MgSO ₄ , 0.11% CaCl ₂ , 97.1%
Erosion rate in water) measured over 3 days
It was 4mm / 24h.

Example 2 90% PEG 20,000 and 10% PEG 400 monostearate (HLB
A segment containing 75% matrix material and 25% patent blue was made in the same manner as described in Example 1, except that a matrix material consisting of 11.5) was used. The erosion rate in synthetic urine was measured at 8 days and was a constant 1.3 mm / 24 h.

The presence of a continuous crystalline phase consisting of PEG20,000 and PEG400 monostearate dispersed therein could be seen under a microscope at 50-125X magnification. Since it was colored with this monostearate fat-soluble blue colorant, it was easily visible. The PEG400 monostearate is distributed substantially evenly throughout the crystals of the polymer, while at the same time filling the intergranular and intergranular cracks and interfaces to repair them.

Example 3 10.8 g PEG35,000 and 3.6 g PEG400 monostearate
Mix while heating at 60-80 ° C until molten. 9.6 g of microcrystalline theophylline was mixed with the molten matrix material and evenly distributed. The obtained molten matrix was extruded into a pre-made Teflon tube having an inner diameter of 6 mm and allowed to cool. The cooled matrix was then piston extruded from the tube and the resulting rod was coated with a 20% solution of polyurethane [Estane 5712F30] in acetone. The coated rod was then cut into 20 mm long segments.

Release of theophylline from the resulting dosage form was determined by combining the dosage form with synthetic intestinal fluid [Revolyt; Composition: 22 mmol /
Bicarbonate ion, 15mmol / potassium ion, 60m
mol / chlorine ion, 3mmol / magnesium ion,
67 mmol / sodium ion and 3 mmol / sulfate ion] in 100 ml (34 g /) of the solution, and then at 37 ° C. for 28 hours,
It was measured by constant shaking (64 rpm) on an orbital shaker. A sample is taken every 2 hours to give a Perk
in Elmer HPLC instrument high performance liquid chromatography (HPL
It was measured in C).

The measured values of the released amount of tetophylline under these conditions were as follows.

Release time (hour, hr) Release amount (μmol /) 0-2 1380 2-4 1220 4-6 940 6-22 6520 (= 815 / 2h) 22-24 1055 24-26 850 26-28 810 Under the same conditions The erosion rate of the matrix was 0.44 mm / h at either end of the dosage form.

Example 4 25% PEG 35,000, 12.5% PEG 10,000 and 12.5% PE
G400 monostearate was mixed with heating at 60-80 ° C, and 49% gentamicin sulfate (powder) and 1% tartrazine were added to the resulting molten mixture to evenly distribute. The molten matrix was extruded into a prefabricated Teflon tube having an inner diameter of 5 mm and allowed to cool. The tube was then cut into 20 mm long segments.

The release of gentamicin sulfate from the resulting dosage form was measured as described in Example 3 except the release was measured spectrophotometrically at 430 mm using a Beckman DU-R spectrophotometer. .

The release amount of gentamicin sulfate was 10 to 15 mg / h as measured over a period of 10 hours, and the erosion rate of the matrix was 1 mm / h.

Example 5 60% 36% PEG35,000 and 24% PEG400 monostearate
Mix while heating at ~ 80 ℃, to the resulting molten mixture,
39% gentamicin sulfate (powder) and 1% Patent Blue V were added and evenly distributed. The obtained molten matrix was extruded into a pre-manufactured Teflon tube having an inner diameter of 5 mm and allowed to cool. The tube was then cut into 20 mm long segments.

The amount of gentamicin sulfate released from the obtained dosage form was 63%.
Substantially the same as described in Example 4, except that it was measured at 8 nm, resulting in 10-14 for 8 hours.
It was mg / h.

Example 6 By a method similar to that described in Example 5, except using PEG35,000 and PEG400 monostearate as matrix materials and neomycin sulfate as the active substance.
A tube segment was made containing 33.3% PEG 35,000, 33.3% PEG 400 monostearate, 32.3% neomycin sulfate and 1% tartrazine.

The amount of neomycin sulfate released from the obtained dosage form was measured in the same manner as described in Example 4, and was 8-10 mg / h.
The matrix erosion rate is 2 m at either end.
It was m / 6h.

Example 7 Block Copolymer of Ethylene Oxide and Propylene Oxide [Synperonic F-8 from ICI
8] of 2] and 2 g of polyethylene glycol 400 monostearate were mixed while heating at 60 to 80 ° C until melted. 2 g of Patent Blue V was mixed with the molten matrix material and the resulting mixture was extruded into a prefabricated Teflon tube (4 mm diameter) and allowed to cool. The tube was then cut into 20 mm long segments, leaving both ends open. As a result of measuring the erosion rate in the synthetic urine, it was 1.2 mm / 24h which was constant over 8 days.

Example 8 0.38 g of D6210 (1,3-divinyltetramethylsiloxane obtained from Petrarch) was added to 4 g of methylhydro-dimethylsiloxane copolymer (PS123 obtained from Petrarch).
And mixed at room temperature. 3 g of salsolve 84 in the resulting mixture
(Salsorb84) (modified polyacrylic acid, particle size 90 ~ 850μ
m, capacity (in 0.9% NaCl): 45g / g, Allied Colloids Lt
(obtained from d.), then 4.72 g of erythromycin estrate and 0.4 g of catalyst solution (mixture of 10% cyclic vinylmethylsiloxane and 90% vinyldimethyl-terminated polydimethylsiloxane). And 1% patent blue were added and mixed. The resulting matrix mixture was extruded into a prefabricated Teflon tube with an inner diameter of 6 mm and cured at room temperature for 4 hours. The tube was then cut into 20 mm long segments.

The amount of erythromycin estrate released from the obtained dosage form was determined in Example 3 except that the dosage form was immersed in 100 ml of synthetic gastric fluid (pepsin-HCl, pH 3) (the above synthetic intestinal fluid was added as a buffer). Measurements were made as described.

As a result of measurement using patent blue as an indicator, the release amount of erythromycin estrate was 9 to 10 mg / h, but it decreased to about 7 mg / h in 24 hours. Under the same conditions, the erosion rate of matrix was 16.5 mm / 24 h.

Example 9 0.19 g of 1,3-divinyltetramethylsiloxane (Petrar
D6210) obtained from CH, and 2 g of methylhydro-dimethylsiloxane copolymer (PS123 obtained from Petrarch)
And mixed at room temperature. 5 g of carboxy-in the resulting mixture
Methyl-cellulose (A250 from Aqualon) was added, followed by 5 g gentamicin sulfate, 0.4 g catalyst solution (10% cyclic vinylmethylsiloxane containing 0.03% platinum and 90% vinyldimethyl groups). (A mixture of polydimethylsiloxane terminated with). The obtained matrix was extruded into a pre-made Teflon tube having an inner diameter of 4 mm and cured at room temperature for 2 hours. The tube was then cut into 20 mm long segments.

The amount of gentamicin sulfate released in the synthetic gastric juice was measured in the same manner as in Example 8 and the result was 1.3 mg / h. The erosion rate of the matrix was 6 mm / 24 h.

Example 10 Comparative Examples with Various Compositions a) Compositions containing pure PEG were prepared by extruding molten PEG 10,000 into prefabricated Teflon tubes (diameter 4 mm). After cooling, the matrix was removed from the tube by the piston and the resulting rod was
% Polyurethane (Estan 5712F30) in acetone solution. The coated rod was then cut into 10 mm long segments. The erosion rate of PEG in the synthetic intestinal fluid (Example 3) was 4 mm / h.

b) A composition was prepared and the erosion rate was measured as in a) above, except that the PEG was PEG 35,000. The erosion rate was 1.8 mm / h.

c) A mixture of 95% PEG35,000 and 5% PEG400 monostearate was melted, and a coated rod was prepared in the same manner as in a) above using a Teflon tube having a diameter of 6 mm prepared in advance. The measured erosion rate in synthetic intestinal fluid was 1.45 mm / h.

d) A mixture of 75% PEG 35,000 and 25% PEG 400 monostearate was melted. Dextrin was added as a filler in an amount of 40% based on the total weight of the composition. The obtained mixture was extruded into a Teflon tube (diameter 10 mm) prepared in advance, and a coated rod was prepared in the same manner as in the above a). The measured erosion rate in synthetic intestinal fluid was 0.34 mm / h.

e) A mixture of 75% PEG 35,000 and 25% PEG 400 monostearate was melted. To the molten mixture was added a mixture of dextrin as a filler and morphine / hydrochloric acid as the active substance, the amount of dextrin and morphine / hydrochloric acid was 40% based on the total weight of the composition. A composition containing 3.55% morphine / hydrochloric acid was extruded into a prefabricated Teflon tube (diameter 6 mm). The resulting rod was coated as in a) above and cut into 10 mm long segments. HP of the release amount of morphine and hydrochloric acid in synthetic intestinal fluid
As a result of measuring by LC, it was 1 mg / h over 10 hours, and the erosion rate was 0.43 mm / h.

f) A composition was prepared in the same manner as in e) above, except that the content of morphine / hydrochloric acid was 9.54%. The amount of morphine / hydrochloric acid released in synthetic intestinal fluid was measured by HPLC.
It was 3 mg / h over 10 hours and the erosion rate was 0.48 mm / h.

g) A mixture of 75% PEG 35,000 and 25% PEG 400 monostearate was melted and mixed with an amount of 3.55% tartrazine. Prefabricated Teflon tube (diameter 6m
m) was extruded, coated as in a) above, and cut into 12 mm long segments. Erosion rate in synthetic intestinal fluid is 4
There was a constant 1.5 mm / h from each end over time.

h) 10.5 g PEG35,000 and 3.5 g PEG400 monostearate were melted and mixed. 6.0 g of methotrexate was added to give a mixture consisting of 52.2% PEG35,000, 17.5% PEG400 monostearate and 30% methotrexate (MTX). The molten mixture was extruded into a prefabricated Teflon tube (diameter 4 mm) to prepare a coated rod in the same manner as in a) above. MTX in synthetic urine (Example 1)
As a result of HPLC measurement of the release amount of
It was 1.5 mg / h and the erosion rate was 0.5 mm / h.

i) 5.4g PEG35,000 and 1.8g PEG400 monostearate were melted and 4.8g dextrin / tartrazine (99: 1).
Were mixed. The obtained mixture was extruded into a Teflon tube (diameter 6 mm) prepared in advance and coated in the same manner as in the above a). Erosion in synthetic intestinal fluid was 0.34 mm over 12 hours as measured by a spectrophotometer at a wavelength of 430 nm.
It was / h.

j) 1g PEG35,000, 0.5g PEG400 monostearate,
And 1 g of the diacetylated tartaric acid ester of monoglyceride and diglyceride (Dat-S from Grindsted Products, Denmark) were melted together. Then 2.5 g sucralfate was added and the resulting mixture was extruded into a prefabricated Teflon tube (6 mm diameter). As a result of measuring the erosion in the synthetic intestinal fluid, it was 1 mm in 8 hours.

k) The same composition as j) was made except that no diacetylated tartaric acid ester was used. 4g PEG 35,000 and 2
g of PEG400 monostearate was melted and 4 g of sucralfate was added to the resulting molten mixture. The obtained mixture was extruded into a Teflon tube (diameter 6 mm) prepared in advance and coated in the same manner as in the above a). Erosion in synthetic intestinal fluid was greater than 2 mm in 8 hours.

l) 5 g of PEG35,000 was melted and extruded into a pre-made Teflon tube (diameter 6 mm). Insert one end of the tube into
Immersed in molten PEG 1500 containing 5% tartrazine.
The composition was removed from the tube and coated with Estane F30, one end of which was dipped into a mixture of PEG 1500 and Tartrazine to coat. The resulting composition was then cut into 7.5 mm lengths. When eroded in synthetic intestinal fluid, the solution turned yellow after 4 hours, and the erosion rate was about 1.9 mm / h.
Met.

m) 2.25 g PEG35,000 and 0.75 g PEG400 monostearate were melted and 2 g dextrin was added (40% dextrin). The obtained mixture was extruded into a Teflon tube (diameter 6 mm) prepared in advance. 3.5 mm with one end coated with PEG1500 + tartrazine according to the method of l) above
Long rods were made and then eroded in synthetic intestinal fluid. It was colored yellow after 8 hours, and the erosion rate at that time was about 0.23 mm / h.

Example 11 A composition was prepared as described in Example 3, except that the rod was cut into 12 mm long segments. The rods obtained were 195 mg PEG35,000, 65 mg PEG4.
It contained 00 monostearate and 170 mg of microcrystalline theophylline. The in vitro erosion rate measured in the same way as described in Example 3 was 1 mm / h. This corresponds to the release of about 15 mg of theophylline per hour. The exact amount of theophylline released was measured by HPLC and the results are as follows.

Release period (hr) Release amount (μmol /) 0-2 2575 2-4 1740 4-6 1645 6-8 1740 The amount of theophylline released from this composition in vivo was determined by 6 patients [3 males and 3 males]. 3 women, ages 18 to 42 years (average age 30 years), weight 63 to 85 kg (average weight 66 kg), all patients examined were diagnosed with bronchial asthma.

The first dose was given to the patient before breakfast (ie in the fasted state) with 2 units of the composition (340 mg) of theophylline with 100 ml of liquid. The second administration was carried out by intravenous injection (Theo-Dur 20mg / ml) of theophylline over a period of 10 minutes at a dose of 5mg / kg ideal body weight in the morning at least 3 days later, and serum of theophylline of each patient was administered. Half-life was measured. Oral administration of venous blood samples to 0,1,2,3,4,5,6,
Samples were collected after 8, 10, 12, 14, 16 and 24 hours. Serum samples were given intravenously, 0, 15, 30, 60 and 90 minutes later, and 2, 3, 5, 7, 9
And after 11 hours. The serum part of the blood sample is -20
Immediately frozen at ° C and stored frozen until analyzed 2 weeks later. The amount of theophylline in serum was assayed by HPLC with an accuracy of ± 5%. The measured serum concentration values and calculated serum half-life values for individual patients are shown in the table below.

Example 12 The in vivo release of morphine hydrochloric acid from the composition of Example 10e) was determined using two subjects [both healthy 40 year old male,
85 kg (No. 1 patient) and 65 kg (No. 2 patient)]. A composition containing 10 mg morphine hydrochloride was administered with 100 ml liquid 2 hours after breakfast. Serum concentrations of morphine hydrochloride were measured hourly from venous blood samples, then stored by cooling until the next day, at which time the serum portion was separated and frozen at -20 ° C. The serum concentration of morphine hydrochloride was analyzed after 3 weeks using the RIAS method,
Both free and conjugated morphine HCl were measured with an accuracy of ± 5% and a sensitivity of 2 ng total morphine HCl / ml serum. The following serum concentrations of morphine hydrochloride were found.

Example 13 18% PEG 20,000, 27% PEG 35,000 and 15% PEG 400
The monostearate was mixed with heating at 65-75 ° C and 40% gendamicin sulfate was added to the resulting molten matrix material and mixed until evenly distributed. A Teflon tube (diameter 4 mm) made in advance of the obtained molten mixture
It was extruded inside and allowed to cool. The resulting rod was then extruded from the tube using a piston, the rod was cut into pieces with a length of 15 mm or 30 mm and dipped in a 20% solution of Estane 30 for coating, but one end was left uncoated. It was
The amount of gentamicin sulfate released from the obtained composition was
In vitro measurements were performed in much the same way as described in Example 3 using the biological agar hole diffusion method to assay for gentamicin sulfate. The release amount of gentamicin sulfate is 14mg / 72hrs
Met.

Erosion rate measurement from the open end of the composition is 1mm / 24hr
It was s, which was the amount of gentamicin sulfate released, 5 mg
Equivalent to / 24 hrs.

A urinary balloon catheter (Ruch, ZF,
It was glued to the tip of 5 ml, size 12). The diameter of its tip is the same as the diameter of the catheter and the length of the composition is
It was 30 mm.

The amount released in vivo was tested in an animal model. SPR Danish
A landrace XY Yorkshire LYY sow (body weight: 22 kg) was used. The pig was housed in a wire mesh cage with a stainless steel tray for collecting urine. Pigs have sedaperone (im) and hypnodil (Hypnod).
The catheter was introduced into the bladder while being anesthetized with il) (ip). At that time, atropine (im) was administered to prevent salivation. 20 ml of urine was collected from the tray every 24 hours, and the urinary concentration of gentamicin sulfate was determined to be 0.2 μg of gentamicin sulfate / by using the biological agar diffusion method.
It was measured by the sensitivity of mg urine. The concentration of gentamicin sulfate was as follows.

μg gentamicin sulfate / ml urine 0-24hrs 1.75 24-48hrs 1.40 48-72hrs 1.55 Dissection on the 4th day revealed slight bleeding outside the bladder. The mucosa of the bladder and urethra was found to be normal.

Example 14 The same animal experiment with pigs as in Example 13 above was repeated with the same composition. In this experiment Argyle silicone balloon catheter (12ch, 5ml, lot number 027603)
Was used. Each catheter was fitted with a cylindrical, 15 mm long composition, but the tip diameter was the same as the catheter diameter. The experiment lasted 7 days. 2 pigs (weight 20 kg and 21
Kg) was used. The following concentrations of gentamicin sulfate were found.

The release of gentamicin sulphate from the catheter was probably blocked in pig # 1 from day 5 onward. Because when the catheter was taken out on the 7th day,
This is because the composition was only reduced to 1/2.

Upon dissection on day 8, there was evidence of irritation in the mucosal tissue in the triangular area of No. 1 pig. This was probably caused by the presence of the catheter tip in the bladder. In pig # 2, the bladder mucosa and urethral mucosa were found to be normal.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References Special Table Sho 61-502759 (JP, A) “Pharmaceutical Development Basic Course ▲ XI ▼, Pharmaceutical Manufacturing Method (above)” Kyosuke Tsuda 1st Edition, 1969 First edition issued on July 10, Jishin Shokan Co., Ltd., P. 135-6,149

Claims (21)

[Claims] 1. The following essential components a), b), c), a) a matrix of crystalline polyethylene glycol polymer having a molecular weight of at least about 20,000 daltons, and b) the crystalline polymer and a nonionic emulsifier. 2 to
A nonionic emulsifier or a mixture thereof dispersed in the crystalline polyethylene glycol matrix in an amount of 50% by weight (provided that the nonionic emulsifier has at least one region compatible with the crystalline polyethylene glycol polymer). And fatty acid esters or fatty alcohol ethers), and c) substantially uniformly dispersed in the crystalline polyethylene glycol matrix and / or geometrically well defined regions within the composition. Active in the aqueous phase by erosion of one surface layer of the composition consisting of at least one active substance located in the and optionally a filler dispersed in a matrix, at a substantially constant and pH independent rate A controlled release composition of matter. 2. The crystalline polyethylene glycol is about
20,000 to about 500,000 daltons, generally about 20,000 to about 100,0
The composition of claim 1 having a molecular weight of 00 daltons, more generally about 20,000 to about 50,000 daltons and especially about 20,000 to about 35,000 daltons. 3. The active substance is a drug for humans or livestock,
A composition according to claim 1 or 2 which is a vitamin or other nutrient enhancer, antiseptic, deodorant or other substance continuously administered to the aqueous environment. 4. The composition according to claim 1, wherein the active substance is a pharmaceutically active powder. 5. The pharmaceutically active powder is from about 0.1 μm to about 500.
μm, typically about 0.5 μm to about 300 μm, more typically about 1
A composition according to claim 4 having a particle size of between about µm and about 200 µm, especially between about 5 µm and about 100 µm. 6. A composition according to claim 1, wherein the active substance is present in the composition in an amount of up to about 60% by weight, generally up to about 50% by weight. 7. The nonionic emulsifier comprises 12 to 24 carbon atoms,
Fatty acid esters and / or aliphatic alcohol ethers having a carbon chain generally consisting of 12 to 20 carbon atoms,
(For example, of esters of palmitic or stearic acid and / or ethers of palmityl alcohol or stearyl alcohol, and / or esters or ethers of polyglycols such as esters or ethers of polyethylene glycol, and / or esters or ethers of sorbitan. 7. A composition according to any one of claims 1 to 6 consisting of such esters or ethers of sugars and / or polyethylene glycol stearate). 8. The nonionic emulsifier is about 5 to 50% by weight of the crystalline polymer and the nonionic emulsifier, generally about 10 to 40% by weight, more generally about 15 to 35% by weight, for example about 20 to 20%. A composition according to any one of claims 1 to 7, which is present in an amount of 30% by weight. 9. A matrix of substantially constant surface area, such as the shape of a cylindrical rod, that can be exposed while the matrix is eroded, and during the intended release period. 9. A composition according to any one of claims 1 to 8 having a coating which is substantially insoluble in a liquid such as body fluid and impermeable to such liquid, the coating having openings at one or both ends. 10. A coating comprising a matrix of one or more substantially water-soluble crystalline polymers and a nonionic emulsifier, the coating eroding the aqueous phase significantly slower than the matrix material containing the active substance. A coating that is exposed to a substantially constant area of the matrix containing the active agent while the composition is being eroded, and the coating is substantially eroded when the matrix containing the active agent is eroded. 10. The composition of claim 9, which is eroded by the heat. 11. The composition of claim 9 wherein the coating is a coating that disintegrates or breaks after its matrix has been eroded. 12. A composition according to claim 9 in the form of a hollow cylinder, a hollow hemisphere, a tablet or a plate. 13. A composition comprising: a) a matrix of crystalline polyethylene glycol polymer having a molecular weight of at least about 20,000 Daltons and a filler optionally dispersed in the matrix, the crystalline polymer and a nonionic emulsifier. On the other hand, a nonionic emulsifier or a mixture thereof dispersed in the crystalline polyethylene glycol matrix in an amount of 2 to 50% by weight (provided that the nonionic emulsifier is at least compatible with the crystalline polyethylene glycol polymer). Fatty acid esters or fatty alcohols), optionally at least one active substance substantially homogeneously separated in said crystalline polyethylene glycol matrix, b) at least about 20,000 daltons Crystalline polyethylene glycol having a molecular weight, the crystalline polymer and The nonionic emulsifier or a mixture thereof dispersed in the crystalline polyethylene glycol in an amount of 2 to 50% by weight based on the amount of the cationic emulsifier (provided that the nonionic emulsifier is compatible with the crystalline polyethylene glycol polymer). Substantial layering a) comprising at least one region, which is a fatty acid ester or an aliphatic alcohol ether) and optionally a homogeneously dispersed active substance in a matrix consisting of fillers And b), the composition being in the form of a cylindrical rod, during the intended release period:
Has a coating that is substantially insoluble in liquids such as body fluids and impermeable to such liquids, the coating having openings at one or both ends, and the composition comprises (i) a crystalline weight of layer a). When the coalescing matrix consists of the active substance uniformly dispersed therein and / or layer b)
The active substance of (ii) causes a substantially zero-order release of the active substance when dispersed substantially homogeneously in the crystalline polymer matrix, and / or (ii) the active substance in layer b) has a crystalline weight. A composition according to claim 1 adapted to provide a tightly controlled pulsatile release of the active substance in layer b) when it is not evenly dispersed in the coalescing matrix. 14. A composition according to claim 13, wherein each of the alternating layers comprises two or more different active substances. 15. The composition according to claim 1, wherein the active substance is an analgesic. 16. A crystalline polyethylene glycol polymer having a molecular weight of at least about 20,000 daltons and a nonionic emulsifier or mixture thereof in an amount of 2 to 50% by weight, based on the crystalline polymer and the nonionic emulsifier. However, the surfactant has at least one region compatible with the crystalline polymer and is a fatty acid ester or an aliphatic alcohol ether), and at least one active substance,
And optionally in combination with a filler, substantially non-uniformly dispersed in the crystalline polymer phase and / or in the composition with the nonionic emulsifier or mixture thereof dispersed in the crystalline polymer phase. Of the active substance located within the geometrically well-defined region of the crystalline polymer and the nonionic emulsifier are sufficient to melt the polymer. Heating at temperature and mixing with stirring to give a substantially homogeneous mixture, the active substance is added to the molten mixture of polymer and nonionic emulsifier or added to the mixture before heating. The resulting mixture is then molded and cooled, for example, by extrusion, coextrusion, injection molding or compression molding, with a substantially constant and pH independent rate of one surface layer of the composition. Activity in the aqueous phase due to erosion of Method for producing a composition for controlled release of substances. 17. A coating is coextruded with a matrix and an active substance, or the matrix and the active substance are injection molded, compression molded or extruded and then sprayed or dipped for dip coating or solvent coating. The method of claim 16, wherein the composition is molded. 18. A coating comprising a matrix of one or more substantially water soluble crystalline polymers and one nonionic emulsifier, the coating being substantially more than a matrix material containing an active agent. A coating that erodes at low rates into the aqueous phase, such that while the composition is eroding, a substantially constant area of the matrix containing the active agent is exposed, so that the coating will not attack the active agent. 18. The method of claim 16 or 17, wherein the matrix it contains is substantially eroded when it is eroded. 19. A composition comprising: a) a matrix of crystalline polyethylene glycol polymer having a molecular weight of at least about 20,000 daltons and a filler optionally dispersed in the matrix, the crystalline polymer and a nonionic emulsifier. On the other hand, a nonionic emulsifier or a mixture thereof dispersed in the crystalline polyethylene glycol matrix in an amount of 2 to 50% by weight (provided that the nonionic emulsifier is compatible with the crystalline polyethylene glycol polymer). Having at least one region and being fatty acid esters or fatty alcohols), optionally at least one active substance substantially uniformly separated in said crystalline polyethylene glycol matrix, b) at least about 20,000 daltons A crystalline polyethylene glycol having a molecular weight of The nonionic emulsifier or a mixture thereof separated into crystalline polyethylene glycol in an amount of 2 to 50% by weight with respect to the crystalline emulsifier (provided that the nonionic emulsifier is compatible with the crystalline polyethylene glycol polymer). Substantial layering a) comprising at least one region, which is a fatty acid ester or an aliphatic alcohol ether) and optionally a homogeneously dispersed active substance in a matrix of fillers. And b) are alternately injected or extruded to have a coating in the form of a cylindrical rod which is substantially insoluble in and impermeable to liquids such as body fluids during the intended release period, When this coating has openings at one or both ends and (i) the crystalline polymer matrix of layer a) consists of the active substance uniformly dispersed therein. And / or when the active substance of layer b) is dispersed substantially homogeneously in the crystalline polymer matrix, causes a substantially zero-order release of the active substance and / or (ii) in layer b) When the active substance is not evenly dispersed in the crystalline polymer matrix,
17. The method according to claim 16, comprising forming a composition which is applied to provide a tightly controlled pulsatile release of the active substance in layer b). 20. An individual unit of the composition made according to any of claims 16 to 19 is combined into a multi-unit medical preparation with controlled release of the active substance in the form of a capsule or tablet. ~ The method according to any one of 19 to 19. 21. The method according to claim 16, wherein the active substance is an analgesic.