JPS619A - Hydrogel device containing active drug having sigmoidal concentration curve of active drug concentration distribution for improved constant release, manufacture and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to a hydrogel device containing an active agent which, upon contact with an aqueous medium, is released at a controlled rate over a period of time by diffusion into the aqueous medium. , a method of manufacturing such a device, and a method of using such a press to release an active drug into an aqueous medium.

[Conventional technology]

Various devices are known in the art for the sustained release of active agents. For example, a monolithic device for the sustained release of a drug, in which the drug is uniformly dispersed in a non-swellable, homogeneous and non-porous polymer matrix, and the drug dissolves and permeates into the polymer itself. Something like this is known.

a microporous device, the pores of which contain an active agent-permeable liquid or gel medium, such that the active agent preferentially dissolves and permeates the medium in the pores; Porous devices are also known, and include water-permeable active agent reservoirs in an impermeable matrix; The device is also known.

Characteristically, such devices release the active agent at a high initial rate and then at a decreasing rate as shown in the following equation.

The release of active agent from a drug homogeneously dispersed in a non-swellable homogeneous and non-porous plasticized bilimer matrix by active agent permeation is known as classical Fickian release.
release). This is because this release ξ-turn generally follows Fick's law of diffusion, M = Kt%, where Mt is the amount of active agent released, K is a constant, and t is time. It is from.

U.S. Pat. No. 3,923,939 discloses removing a portion of the active agent from the surface of the prior art diffusion and osmotic rupture device by washing to form an empty layer of polymer matrix. Disclosed. However, these devices are
As shown by the release slope of the diffusion-type device of Example IA, along with that of Example IA, although exhibiting a low initial release, it does not contain a hydrogel and still generally exhibits a Fickian release. The only irregular release turn described and exemplified is that of an osmotic bursting device, in which the bursting device is flushed for 24 hours, as described in U.S. Patent No. 3,923;
As shown in Example 38 of '939 and FIG. 10, the initial release rate is reduced by 90%.

One disadvantage of drug diffusion devices of the type exemplified in Example IB of the said patent is that after treatment of the surface, the drug is not allowed to remain in the device matrix until it is once again uniformly distributed throughout the diffusion device. This means that the drug diffuses at a rate corresponding to the drug substance diffusion rate. As a result, such pharmaceutical substance soluble rubbery polymer systems have a number of drawbacks.

Active agent releasing devices containing swellable hydrogel matrices are also known in the art. In such devices, the active agent is uniformly distributed within the non-swellable or glassy hydrogel polymer. Upon contact with an aqueous environment, the dry hydrogel swells as water penetrates the glassy matrix. The boundary between the glassy phase and the swollen or rubbery phase of the hydrogel is known as the solvent front. As this aqueous solvent front moves inward from the surface to the center of the hydrogel device, the active agent in the rubbery swollen phase of the hydrogel dissolves and diffuses through the swollen phase to the external aqueous environment. The active agent is virtually unable to diffuse appreciably in the glassy, unswollen phase of the hydrogel. The rate of active agent delivery into the aqueous environment is determined by a number of factors, such as the permeation rate of the aqueous solvent front, the shape of the de S.
It depends on the diffusivity of the active agent in the swelling phase, the active agent loading in the hydrogel matrix, the distance between the solvent front and the device surface, the rate of surface area reduction of the glassy phase during solvent infiltration, etc. [e.g. I. Lee, Polymer Communication, Vol. 24, pp. 45-47, 19
1983 (Ping 1. Lee.

POLYMER Omnunication,
Vol, 24, P, 45-47 (1983
))reference〕.

Characteristically, the release rate of such hydrogel devices containing a uniformly distributed active agent is generally determined by the following equation: J = Kta, where J is the amount of active agent released. , K is a constant, t is time and la is between about 08 and 0.5). As a result, such systems do not substantially meet the zero-order release rate requirement because the release rate decreases continuously from a high initial release rate.

[Problem that the invention seeks to solve]

One object of the present invention is an improved device comprising an aqueous swellable hydrogel matrix containing an active drug solute from which the rate of release of the active drug by diffusion is substantially zero order for extended periods of time. It is to provide.

Another object of the invention is to provide such an improved decoder.
It is an object of the present invention to provide a method for delivering an active agent to an aqueous environment at a substantially constant rate over an extended period of time using an S-chair.

[Failure to solve the problem]

These and other objects of the present invention provide a stable heterogeneous concentration distribution of active drug solutes in a hydrogel matrix, wherein the concentration of the active ingredient is gradient perpendicular to the surface of the device, and between that surface and the core of the device. The concentration gradient is essentially continuous, that is, smooth, and contains an inflection point, forming a sigmoidal curve (si
This can be achieved by providing a concentration distribution in the form of a gmoidal curve.

A substantially continuous inflection point-containing sigmoidal concentration distribution of active agent from the surface to the core of the device increases in an upward slope to an inflection point located between the surface and the core, and then from that inflection point to the core. Increases with a downward slope.

Such a sigmoidal curve-containing distribution may occur when the ζ-chair in the hydrogel loaded with the active agent is present in a fully swollen state, e.g. immediately after loading the active agent in the swollen state into the hydrogel and before drying the loading device. You can't get it just by cleaning. This kind of rubbery and fully swollen de? In a chair, removing the active agent, for example by washing its surface, results in a concentration distribution that generally increases in a downward slope from the surface to the core. Such a total distribution is sigmoidal or "
In contrast to the “bell-shaped” concentration distribution, the “parabolic” concentration distribution
olic ) J concentration distribution. Moreover, the parabolic concentration distribution characteristically results in a time-dependent release rate with a decreasing initial rate.

The sigmoidal curve-containing distribution is characterized by the use of a volatile swelling solvent to remove the surface of a hydrogel device uniformly loaded with an active drug solute, which is initially in an unswollen or glassy state, until the solvent reaches the outer surface of the device. If the device penetrates into the external swollen phase, it is washed for a sufficient period of time to remove a portion of the active agent from the Zam phase, and then the active agent is brought to a stable concentration distribution in a manner that increases from the surface to the core of the deguise. was found to be obtained by rapidly removing the volatile solvent from the hydrogel device at a rate sufficient to fix the concentration gradient in the form of a continuous, inflection point-containing/gumoidal concentration curve. .

When the solvent is removed, the swollen phase returns to the non-swellable glass state. Therefore, the diffusivity of the active drug solute is characteristically at least several orders of magnitude lower in glassy hydrogels than in swollen or rubbery hyProgels, so that the desired concentration distribution can be achieved in a storage-stable product.
obtained as.

The processing conditions and the nature of the swelling solvent are selected to obtain the desired distribution so that when the dried glassy hydrogel is placed in the aqueous hydrogel swelling environment for subsequent use, the improved desiccant is regulated. The active agent is released at a substantially constant rate over a period of time. Such processing parameters for active agents are time and temperature. For a constant temperature, the amount of permeation of the expansion solvent is time dependent. Similarly, the rate of diffusion of the active agent in the swollen portion of the hydrogel increases with increasing temperature, just as the rate of penetration of the solvent front increases.

Therefore, in some cases accelerated extraction of a portion of the active agent through the use of high temperature conditions is desirable. Also, stirring of the swelling solvent and removal of the active agent-containing swelling solvent, e.g. by washing, during the extraction of the active agent from /l or initially uniformly loaded HyPlogel devices may be advantageously used. I can do it. Generally, the extraction temperature is between the freezing and boiling points of the selected volatile swelling solvent, e.g.
It can vary widely between about 120°C. If desired, superatmospheric pressure conditions can be used during the extraction step. Desirably, the temperature of the extraction step is selected to be below the glass transition temperature of the loaded hydrogel. If the temperature of the extraction step is greater than the glass transition temperature of the loaded hydrogel, the diffusion rate of the active agent in the unswollen portion of the device increases significantly.

Therefore, it is preferred that the extraction temperature be between about -20<0>C and about 120<0>C, but not exceeding the glass transition temperature of the loaded hydrogel. The glass transition temperature of the loaded hydrogel is
Depending in part on the nature of the hydrogel selected, temperatures of about 45°C to about 1.20°C or higher are generally preferred. More preferably, a hydrogel having a glass transition temperature of 50°C or higher is used and the extraction step is carried out between about 10°C and 50°C.

Because the controlled extraction swells only the exterior of the device, it is important that there is a residual unswollen core to obtain the desired sigmoidal concentration distribution. Generally, between about J5 and 98% by volume of the Zino S chair, the distribution improvement (pro
The file modifica(ion) treatment causes at least partial swelling, preferably about 20 to 90% by volume at least partially swelling. Thus, about 7 to 80% by weight of active agent, preferably 15 to 75% by weight, relative to the amount of active agent initially present, is removed from the loaded hydrogel.

Fixing the active agent in the desired concentration distribution (immobi
Therefore, it is a very important aspect of the invention that the sigmoidal concentration distribution obtained during the extraction step is retained during the solvent removal step. About this.

This is accomplished by rapidly removing the swelling solvent from the swollen portion of the hydrogel matrix. Fast removal here means that the rate of removal of the swelling solvent is substantially greater than the rate of diffusion of the active agent in the swollen portion of the hydrogel.

Advantageously, the desired rapid removal of volatile swelling solvents can be achieved by reducing the pressure of the system under isothermal or adiabatic conditions and removing the solvent by evaporation. The degree of pressure reduction depends on the nature of the volatile swelling solvent and the temperature. High vacuum is desirable because it is desirable to deflate the solvent quickly to minimize active agent diffusion.

Advantageously, the pressure is below 70 x HJ, preferably below 10 Hg, most preferably below 0.1 m*H,! It is lowered to 9 or less. A pressure drop of less than 10 x 10-3i+mHg is highly desirable. Pressure reduction can be achieved under substantially adiabatic conditions, under moderate heating conditions, or with cooling. Temperatures above the glass transition temperature should generally be avoided to minimize diffusion of the active agent. In addition, to ensure that the active agent is fixed in the desired sigma-like concentration distribution between the DEIS surface and the DEIS core while rapidly removing the volatile swelling solvent, low pressure and simultaneous Lower temperatures are usually advantageous. The adiabatic rapid drop in pressure is a feature that reduces the temperature of the device considerably, thereby helping to fix the desired distribution. Conventional freeze drying conditions can be used.

Hydrogels useful in the present invention are generally all water-swellable, but water-insoluble polymers. Such polymers are synthesized, for example, by free radical copolymerization of a water-soluble vinyl monomer and a difunctional crosslinking agent, and the crosslinked polymers hydroxyethyl methacrylate and ?
Livinylvirolin is the two most widely known and used hydrogels, but other water-soluble monomers, along with various comonomers and crosslinking agents, can be used to make hypogels.

Particularly useful are hydrogels obtained by copolymerization with macromeric crosslinkers, as described in US Pat. No. 4,192,827. Other useful hydrogel compositions include U.S. Patent No. 8.220.96
No. 0, No. 3.520.949 and No. 3.503
．． No. 942.

Water-soluble pinyl monomers useful in the production of hydrogels, including, but not limited to, hydroxyalkyl esters and amides of acrylic and methacrylic acids;
For example, 2-hydroxyethyl acrylate or methacrylate, 2- and 3-hydroxyzolobyl acrylate and methacrylate; 2,3-u hydroxyzolobyl methacrylate; and structural formula: c, where R and W are hydrogen; It is methyl or ethyl, and n is an integer of 2 to 5o. ). Hydroxyalkyl monoesters and diesters of maleic acid or hexamaric acid, as well as hydroxyalkyl vinyl ethers, 2-hydroxyethyl vinyl ether and 4-hydroxybutyl vinyl ether, and their ethoxylated derivatives, e.g. [7-2-hydroxyethyl maleate and fumarate; and 2- and 3-hydroxyzorobyl butyl fumarate are similarly useful. Other useful monomers are N-vinyl vinyl 017r
and N-vinylpyrrolidine, 4- and 2-vinylpyridine; N,N-dialkylamino esters and amides of acrylic and methacrylic acids, such as N,N-
Dimethylaminoethyl methacrylate and methacrylic acid, such as N,N-dimethylaminoethyl methacrylate and methacrylamide; N,N-dimethyl"fmi/
Ethyl vinyl ether, N-mefo-A/acrylamide 1, acrylic acid, methacrylic acid, sodium-styrene and sodium vinyl sulfonate, acrylamide and methacridiamide.

These monomers can be used alone and in combination with each other and can also be copolymerized with suitable hydrophobic vinyl monomers such as styrene, acrylates and methacrylates, vinyl esters and vinyl ethers. Maleates, fumarates and hyphenyl ethers require the presence of a comonomer for polymerization to proceed. Also useful are crosslinked or linear polyvinyl alcohols and vinyl alcohol copolymers with ethylene, acrylates, vinyl esters, and vinyl, rubyrolidone copolymers with vinyl esters.

What is the crosslinking agent used in the production of the hydrogel?

A di- or polyfunctional vinyl compound with a molecular weight of 200 to 10,000, which can be present in the polymerization mixture in the range α1% (based on the low molecular weight crosslinker) to 60% (based on the high molecular weight crosslinker) .

Other useful hydrogel materials include polyethylene oxide-containing polycondensates, such as diisocyanates and
Polyester obtained from polyurethane dioic acid, diacid chloride or anhydride obtained from polyethylene oxide diol of 0 to tooo and polyethylene oxide diol having a molecular weight of 300 to 10,000; derived from maleic acid or 7-malic acid and polyethylene oxide diol, Unsaturated polyesters copolymerized with styrene or acrylic monomers to form crosslinked polymers; epoxy polymers derived from diepoxides and 3-aminozolobyl ethers of polyethylene oxide diols; and diacids, diacids, b'- and anhydrides substance and molecular weight 300-10
000 polyethylene oxide diol and 3-aminozorobyl ether. According to those skilled in the art of polycondensation, any number of polyethylene oxide polymers containing a number of co-reactants preferably having at least 10% by weight of polyethoxy units can be classified as hydrogels. It can be manufactured while Polycondensation hydrogels are, for example,
No. 3,822,238;

In this connection, it has been found that unsaturated polyesters based on maleic anhydride and alkylene diols can be copolymerized by free radical initiation with water-soluble vinyl monomers, vinylpyrrolidone, 2-hydroxyethyl methacrylate, or hydroxyalkyl-vinyl ethers. Also useful are hydrogels.

The hydrogel may contain polysiloxane units, as also described in US Pat. No. 4,186,250, or may contain perfluoroalkyl substituted side chains. Other useful supports include water-swellable polymers derived from natural products, such as cellulose or proteins, such as reconstituted cellulose films, and hydroxyethylcellulose, or esters and albumin-derived polymers. include.

In general, the term "hydrogel" refers not only to cross-linked water-swellable polymers, but also to highly hydrolyzed polyvinyl alcohols, which are poorly soluble or not soluble in the environment in which they are used, and which are practically Also included are linear polymers that form gels. Even water-soluble polymers can be used in the present invention, as long as they do not dissolve during application of the method of the present invention.

The most preferred hydrogels for the practice of this invention are hydroxyalkyl acrylates or methacrylates,
Or, when obtained by suspension polymerization of an N-vinyl-pyrrolidone-containing mixture, they are Tokihiro gel beads. Such beads and methods of making them are described in U.S. Pat. No. 4,224, which is cited as prior art herein.
．． It is described in No. 427.

In the present invention, a hydrogel is defined as a polymer having an effective degree of swelling in water of at least 5% by weight of water.

Pharmaceutical substances used to treat the body, whether local or systemic, can be incorporated as active agents into the carrier of the present invention. "Pharmaceutical substance" is used herein in its broadest sense to include any composition that produces a pharmacological or biological reaction.

Suitable pharmaceutical substances for use in treatment according to the present invention include, without limitation, those listed in US Pat. No. 3,732,865 (columns 10 and 11).

Other pharmaceutical substances having the same or different physiological activity as those mentioned above can also be used within the scope of the invention in the carrier.

Suitable mixtures of pharmaceutical substances can, of course, also be formulated with as much ease as single-component systems.

Pharmaceutical substances can be present in various forms, e.g.
ged ) molecules, components of molecular complexes, or non-acetate, maleate, tartrate, salicylate, etc. forms. For acidic pharmaceutical substances, metal salts, amines or organic cations (eg quaternary ammonium) can be used. Additionally, simple derivatives of drug substances (eg, ethers, esters, amides, etc.) that have the desired retention and release properties but are easily hydrolyzed by the body's pH, enzymes, etc. can be used.

The amount of drug substance incorporated into the carrier will vary widely depending on the particular drug substance, the desired therapeutic effect and the time over which the drug substance is to be released. Since various carriers of various sizes and shapes are intended to provide complete dosing regimens for the treatment of various diseases, there are no critical limits on the amount of medicinal substance incorporated into the carrier. There is no upper limit. The lower limit also depends on the activity of the drug substance and the rate of its release from the carrier.

Therefore, it is impractical to define a range of therapeutically effective amounts of drug substance released by a carrier.

Preferred pharmaceutical substances to be formulated according to the invention are those designed for long-term treatment, so that multiple daily administrations are avoided; examples of these include anaglyxes, such as methandrostenolone; analgesics; , such as acetylsalicylic acid, phenylbutacin or methatone; anprogens, such as methyltestostero/; antibiotics, such as rifampin; anti-depressants, such as imizolamine or maprotiline; antidiabetic agents, such as phenformin; antispasmodics, such as CalA7 Mazevin; antihistamines, such as trihelenamine; antihypertensive agents, such as human 2zazine;
anti-infective agents, such as trimethoprim; anti-parasitic agents, such as nifurtimox; anti-ξ-quinone syndrome agents, such as rezedo-ξ; anti-inflammatories, such as nazoloxene; cough suppressants, such as pensinatate; appetite suppressants, such as machine 1
bronchodilators, e.g. phenotylol; coronary artery dilators, e.g. phenalcomine; corticoids, e.g. dexamethasone;
cs), such as floxuridine; diuretics, such as hydrochlorothiazide; hypnotics, such as glutethimide; stimulants, such as reserpine or thioridazine; mental tonics, such as methylphenidate; agents such as sulfinpyrazone; vasodilators such as isoproterenol.

In addition to pharmaceutical substances, the copolymers of the present invention may be formulated with biocides, including aromatic or food flavoring agents, fungicides, fungicides, insecticides, nematicides and herbicides. .

Other examples of biologically active ingredients include U.S. Patent No. 3.660.
, No. 563 (columns 3 to 7).

It is important that the active agent is sufficiently soluble in the aqueous environment of use, ie is a solute to the aqueous environment, so that upon aqueous activation it will diffuse through the swollen hydrogel to a sufficient extent to achieve the desired effect. be. Preferably, the active agent is substantially solid in the dry state. Because of this, the active agent distribution is obtained in a glassy state, thereby further reducing the amount of diffusion that occurs when it is desired to increase the storage stability of the sigmoidal concentration distribution.

The active agent-loaded hydrogel starting materials of the present invention typically have a uniform active agent concentration and are in a glassy or unswollen state.

Such starting materials are known or readily obtained, for example, by soaking the hydrogel in a solution of the active agent in a solvent or solvent mixture that is a swelling agent for the hydrogel. Suitable swelling agents include water, lower alkanols, lower alkanones, methylene chloride, dimethylformamide, dimethyl sulfoxide, water-lower alkanol mixtures, water-lower alkanone mixtures, etc., and the swelling solvent is removed at atmospheric pressure or under reduced pressure. Ru.

Volatile swelling solutions useful for removing a portion of the active agent from glassy or non-swelling loaded hydrogels include water, lower alkanols of up to 5 carbon atoms, lower alkanones of up to 5 carbon atoms, methylene chloride, and Compatible mixtures thereof are included.

The shape of the hydrogel device is not critical and may be in the shape of a round cylindrical doublet, corneal lens, rod, cube, sheet, tube, etc., although it is generally preferred that the hydrogel device be spherical, eg, bead-shaped.

Preferably, such beads can vary in size from about 0.01 mm to about 20 mm in diameter depending on the desired application.

The improved device of the present invention can be used for aqueous fluids, such as water, body fluids including gastric fluid, lacrimal fluid, intestinal fluid, rainwater, etc.

When activated by soil moisture, seawater, etc., the moisture diffuses into the device and causes the deguise to swell inward from its surface. As these fluids permeate the device, the active agent is swollen and diffuses from the swollen region into the surroundings.

The rate of release therefore depends on the rate of active agent in the swollen region, etc. By taking advantage of this unique active agent distribution, excellent and consistent release rate characteristics can be achieved.

When the improved device containing the active agent in a sigmoidal concentration distribution is activated by placing it in the aqueous environment in which it is used for its intended purpose, the active agent is released in a controlled continuous manner by diffusion. emitted from the device in a manner that

Preferably, at least 40% by weight of the active agent released upon such actuation is released at a substantially constant, yet subzero rate. Most preferably, at least 50% by weight of the active agent is released at a substantially zero order rate. The improved device of the present invention is particularly advantageous for the release of active agents where the effective dosage of the active agent is relatively close to the dosage above which side effects may occur. Unlike prior art systems that have release rates that are initially high, e.g. close to or above the release rate at which undesirable side effects appear, and then taper off below the optimal effective dose release rate plate, the devices of the present invention can be used at any time. The active agent can be released at an optimal release rate while keeping the risk of overdosage to a minimum. Such release rate characteristics are prone to cracking and rupture due to the swelling properties of the gel support.

In one embodiment of the invention, the improved device is in the form of a hydrogel bead, with a core substantially uniformly loaded with active agent extending outwardly from the center of the device and extending beyond the radius of the bead. The sigmoidal concentration gradient of the active agent extends from about 99% to about 30% of the radius) and comprises 0 to about 10% of the radius of the bead. There can be a substantially uniform, at least partially empty outer portion. Within a sigmoidal concentration gradient, the point of inflection is approximately 30% or less, preferably 2% or less, from the center of the gradient in either radial direction.
It can be offset by less than 0%, and most preferably by less than 15%. When a substantially uniform, at least partially empty outer portion is present, preferably no more than 10% by weight of active agent is present per cloud mass compared to the core concentration of active agent.

FIG. 1a shows a representative active agent concentration distribution according to the present invention, where O is the center of the device, D is the reed at its surface, line segment OA represents the radius of the core, and line segment AO is the sigmoidal It represents the radial line segment containing the concentration gradient, the point B represents its point of inflection, and the optionally present line segment CD represents the at least partially empty external part of the device.

Figure 1b shows a typical active agent distribution resulting from simply washing a uniformly loaded, fully swollen hydrogel device, where 0 is at the center of the device and C
' is its surface, line segment OA' represents the radius of the core, and line segment A'C' represents the parabolic concentration distribution.

, [Examples] All compositions in the following examples are expressed in weight percent unless otherwise specified.

Example 1 The hydrogel beads used in this example were made of poly(tetra) with an average molecular weight of 2,000 by end-capping with 2-hydroxyethyl methacrylate (HEMA) 70% hydroisophorone quisocyanate. U.S. Pat. Nos. 4,171,056 and 4,171,056 and U.S. Pat.
27 by reaction with excess HB MA. After polymerization is complete, these beads are filtered and
Before drying, the mixture was extracted with ethanol for 24 hours using a Knoxhlet, classified into standard mesh sizes, and used in the present invention. The dried hydrogel beads have a glass transition temperature (Tg) of about 116°C, an equilibrium water swelling of about 25%, and an equilibrium ethanol swelling of about 49%, as measured by differential scanning calorimetry (DSO). show. Average diameter Li
nt -1, (3+, 18 mesh portion hydrogel beads 2.59% of 50% 0% dilenolol 11 prepared in a mixture of 60% ethanol and 40% water)
Equilibrated in Solution C 12.5.9 for 24 hours. After filtration and very brief washing, the swollen loaded beads were placed under vacuum (0,
1 rough rLHjii) Pharmaceutical substance of 344% 44% ofsujilenolol Ho dried at 50°C and uniformly distributed -
A polymer composite system was obtained. The resulting dried offsudilenolol HC1 loaded beads were divided into five portions and controlled extraction in excess volume of water with stirring at 23° C. for 5, 1.5, 20 and 30 minutes, respectively. One control portion of dry loaded beads was not extracted. Immediately after separating the extraction solvent, the conditioned extraction beads were placed under high vacuum (0,025 iu
tHJi') Freeze-dried for about 15 hours. Such treatment resulted in a 20-minute chromatographic analysis of untreated and unextracted beads, as demonstrated by an experimentally measured 8BM In contrast to the even drug substance concentration distribution in the control (dried hirogerma)
A sigma-like drug substance concentration distribution with a clear inflection point within the IJx is fixed (illustrated in Figures 2a and 2b).

In Figure 3a, oxprenolol Hot from these above-mentioned controlled extraction beads was added in glassware (1n-vi).
tro) is compared with that of the unextracted control. It is clear that an inflection point and constant rate release region (up to 60% of total release) corresponding to an inflection point in the drug concentration distribution exists in the cumulative release curve of the controlled extraction beads of the present invention. This is clearly different from the corresponding unextracted control as such release characteristics are absent.

In addition, Figure 3a shows that the t5o value (time to reach 50% release) is further prolonged (more than 2 times) by the present invention compared to that of the control, and 1 compared to the absence of any time-lag in the unextracted control. The present invention shows that a time lag of less than 13 hours (obtained by extrapolating the linear release region to the time axis) is obtained. Effect of adjusted extraction time on oxzolenolol HOI loading is shown in Figure 3b. With an extraction time of 30 minutes, only about 10% of the drug substance load is removed.

Example 2 This example illustrates the storage stability of the system obtained according to the invention. Example 1 was repeated except that -16+18 mesh beads 75I were used for the initial loading of oxprenolol HOI and only 20 minute and 30 minute controlled extraction beads were prepared in addition to the unextracted control. The amounts of loading solution and extraction solvent used are proportionally increased according to Example 1.

The sample thus obtained was administered in a dose form corresponding to 100η oxprenolol HC1.
s) and stored in capped vials under room conditions. 2
The release distribution in the glassware for samples stored for 5 and 59 days is almost identical to that of samples without storage time. O for the unextracted control and the modified extraction beads of the invention.
A comparison of oxzolenolol HOI release during and 59 days storage is shown in Figures 4a and 4b. The very small changes observed in the release distribution are a direct indication that the sigmoidal drug substance concentration distribution produced by the present invention is maintained virtually indefinitely. The characteristic of long term constant rate release from the conditioned-extracted sample in contrast to the exponential decay of the release rate in the unextracted control is also evident from Figures 4a and 4b.

Example 3 This example demonstrates the modified extraction process of the present invention to produce the desired inflection points, time lags, and constant rate release regions in the cumulative release distribution.

Glassy Pharmaceutical Substance Loaded Hydrogel Matrix Roll H
The ot loading method was utilized. In the medicinal substance solution I) a
Immediately after equilibrating the gel beads, a portion of the swollen, loaded beads was passed through a conditioning-extraction step in water for 30 minutes and then freeze-dried under high vacuum.

Another portion of the swollen, loaded beads was dried before conditioning-extracting in water for 30 minutes and then freeze-dried throughout as described in Example 1. Oxprenolol Hot release in glassware from the latter.

Although the cumulative release curve showed characteristic inflection points, time lags and regions of virtually constant velocity.

The former showed only a slight decrease in the initial release rate compared to the control, and the inflection point, time lag and constant rate region were clearly absent.

Example 4 This example illustrates the need for freeze drying to dry at the temperature at which the desired inflection point, time lag, and constant rate region occur in the cumulative release profile.

Hydrokel beads having a composition similar to that of Example 1 were used except that 65% HEMA instead of 70% and 35% PX instead of 30% were used in the suspension polymerization. The hydrogel beads exhibit a glass transition temperature of about 115° C., an equilibrium water swelling layer of about 20% and an equilibrium ethanol swelling value of about 45%. The hydrogel beads thus obtained were subjected to the same purification, oxzolenol HCI loading and drying steps as in Example 1. Dry loaded beads were conditioned in water for 30 minutes. One portion of the extraction beads was immediately freeze-dried as in Example 1, while the other portion was dried in a vacuum oven under high temperature at 50°C.

Oxzolenolol H in glassware from freeze-dried part
CI release showed characteristic inflection points, time lags, and virtually constant velocity regions in the cumulative release curve;
The sections dried at 50"C showed only a slight decrease in initial velocity compared to the control, with inflection points, time lags and constant velocity regions clearly absent.

Example 5 This example illustrates the effect of different solvents used in the conditioning-extraction process on oxzolenolol HCl release from another glassy hydrogel composition.

The hydrogel beads used in this example were HEMA beads according to U.S. Patent No. 4,2j4,427.
21%, PX (of ash as defined in Example 1) 12%, N
- produced by free radical suspension polymerization of a monomer mixture containing 12% vinyl gyrolidone (MVP), 275% ethylhexyl acrylate (EHA), and 275% methyl methacrylate (MMA). The hydrogel beads exhibit a glass transition temperature of about 99°C, an equilibrium water swelling value of about 12%, and an equilibrium ethanol swelling value of about 60%.

The hydrogel beads thus obtained were subjected to purification, loading and drying steps according to Example 1, except that a 50% oxzolenolol HOI loading solution was prepared in methanol. Uniformly distributed medicinal substance 37
Dry loaded beads containing 4% were controlled extracted for 30 minutes in water or 10 minutes in acetone before freeze drying as in Example 1. The in-glass release of oxprenolol from these control-extracted beads is compared to that of the unextracted control in FIG. 5. In addition to a characteristic inflection point and constant rate release region (less than 60% of total release), a t5o value of 15 times that of the control and approximately 6.5
In contrast, the time lag is obtained by using acetone as the extraction solvent.

Example 6 This example provides a detailed description of the invention by varying the polymer morphology, mesh size, type of drug substance, and loading method.

The Hypogel beads used in this example were the same seven-mer mixture as in Example 5, in which 50% polyzolopylene glycol (molecular weight a, o o o) was dissolved in the monomer mixture as a diluent. It was prepared by free radical suspension polymerization of the monomer mixture. After polymerization is complete,
These beads were filtered and Soxhlet extracted with ethanol for 3 days to remove diluent and residual monomer before drying, and sized to standard mesh sizes for use in the present invention. The HyP gel beads exhibit a glass transition temperature of about 99°C, an equilibrium water swelling value of about 10%, and an equilibrium ethanol swelling value of about 72%.

=30+35 mesh portion of hydrogel beads 2.5.
9, methanol 935 gadeiklofenac (dicl
ofenac) sodium solution 75.9 and tumbled in a capped vial on a vial rotator for 5 hours or until all of the drug substance solution was absorbed by the beads. . The swollen, loaded beads were then dried in a laboratory fluid bed dryer for about 15 hours at room temperature to yield a drug substance-polymer-combosite with a uniformly distributed diclofenac sodium loading of 51.4%. . The dried, loaded beads were conditioned-extracted in water for 10 minutes before freeze-drying as in Example 1. These regulation-in-glassware releases of diclofenac sodium from the extraction beads were observed at a characteristic inflection point, ca.
These features were not observed at all in the unextracted control, which showed a time lag of minutes and a constant rate release region of up to 60% of the total release. Moreover, the t5o value (time to reach 50% release) of these controlled extraction beads was increased by 5 times that of the unextracted control.

Examples 7-9 The method of Example 1 was repeated for hydrogel sheets containing different active agents. In all cases,
The release in glassware from the system obtained according to the present invention is
It showed characteristic inflection points, time lags and long constant rate release regions, whereas these features were completely absent for the unextracted control. The results are summarized in the table below.

Example 10 This example illustrates the need to utilize the present invention in a glassy Hyrogel system.

Ofsu dilenolol HC1 with particle size of 0.5-5 microns
Approximately 11 parts of ethylene vinyl acetate copolymer (3
0% vinyl acetate) ) 37 parts and xylene 52
dispersed in a viscous solution containing 50%. The rubbery ethylene vinyl acetate copolymer used herein has negligible water swellability and a glass transition temperature of about -25°C. The above viscous solution was cast onto a glass plate and then dried to form a film having a thickness of 0.2 mm and an OXF L/10-F HOI loading of 23%. Approximately 1.5 cTl of the loaded ethylene vinyl acetate film was dissolved in 1.5 cTl of acetate/vinyl acetate prior to freeze drying as in Example 1.
Interpartial adjustment was extracted. In-glassware off-sdilenolol HOI release from this controlled extraction sheet was similar to the control, with only a slight decrease in initial release rate compared to the control, with no inflection point, time lag, and constant rate release region. was not recognized at all.

[Brief explanation of the drawing]

Figure 1a shows a typical active agent concentration distribution according to the present invention, and Figure 1b shows a typical active agent distribution resulting from simply washing a uniformly loaded, fully swollen hydrogel gel. , Figure 2a shows a cross-section of beads extracted in water for 20 minutes versus dilenolol HOI.
Figure 2b shows the IMX-ray microzolobe chloride scan results for the unextracted control, oxzolenolol.
Showing the EMX-ray microzolobe chlorine scan results, Part 3a
Figure 3b shows the effect of adjusted extraction time in water on the release of Ofsudilenol l-101 from the hydrogel composition of Example 1 in glassware; Figure 4a shows the effect of oxzolenolol HO before storage.
Figure 4b shows the release rate of oxprenolol HC1 in glassware after 59 days of storage; Figure 5 shows the release rate of oxprenolol from the hydrogel composition of Example 4. 101 shows the effect of extraction solvent on the release of No. 101 into glassware.

Claims (1)

Claims: 1. A controlled release diffusion device containing an active agent having a stable concentration distribution increasing in a gradient perpendicular to the surface of the device and between the surface and the core. It consists of a non-swollen, swellable hydrogel matrix into which the active agent is permeated, the gradient being substantially continuous,
sigmoidal curve shape with an inflection point, such that when placed in an aqueous hydrogel swelling environment, the device releases the active agent in a controlled and continuous manner by diffusion into the aqueous environment for a predetermined period of time. The device, characterized in that it is adapted to emit. 2. Claim 1, wherein the device is bead-shaped.
Devices listed in section. 3. The device of claim 2, wherein the beads have a diameter of about 0.01 mm to about 20 mm. 4. Claim 1, wherein the active agent is a pharmaceutical substance.
Devices listed in section. 5. A device according to claim 3, wherein the active agent is a pharmaceutical substance. 6. The device of claim 1, wherein at least 40% by weight of the active agent is released at a substantially zero-order rate. 7. The device of claim 1, wherein at least 50% by weight of the active agent is released at a substantially zero-order rate. 8. the core is substantially uniformly loaded with an active agent and extends outwardly from the center of the bead to about 1 to about 60% of the radius of the bead, and a sigmoidal concentration gradient of the active agent is present in the core; extending outward from the core to cover about 99 to about 30% of the radius of the bead;
Approximately 10 of the outermost portion of said radius to the surface of this bead
3. A bead-shaped device according to claim 2, wherein the remainder, which is not more than %, is at least partially free of active agent. 9. The device of claim 5, wherein the outermost portion of the radius of the bead contains no more than 10% of the active agent per unit volume compared to the core concentration of active agent. 10. The device of claim 1, wherein the hydrogel is substantially insoluble in the aqueous swelling environment used. 11. The device of claim 10, wherein the hydrogel is a crosslinked water-swellable polymer. 12. a) washing the surface of an unswollen or glassy, uniformly loaded hydrogel device with an active agent with a volatile swelling solvent for a time sufficient to allow the solvent to penetrate the outer surface of the device; has an external swollen or rubbery phase and an internal non-swollen or glassy core;
thereby extracting a portion of the active agent from the rubbery phase to produce a substantially continuous active agent concentration gradient in the shape of a sigmoidal curve including an inflection point; b) an inflection of said continuum; Immobilize the active agent distribution with the shape of a sigmoidal curve containing points
c) removing the volatile swelling solvent from the swollen portion of the device at a rate sufficient to: c) obtaining a non-swellable device obtained. Production method. 13. Extraction step a) is between -20° and about 120°C,
13. The method of claim 12, wherein the method is carried out at a temperature that does not exceed the apparent glass transition temperature of the active agent-loaded hydrogel. 14. The method of claim 12, wherein said volatile solvent removal step b) is carried out at a pressure of 70 mmHg or less. 15. The method of claim 14, wherein volatile solvent removal step b) is carried out under substantially adiabatic conditions. 16. The method of claim 12, wherein about 15 to 98 volume percent of said device is at least partially swollen by a volatile swelling solvent. 17. The method of claim 12, wherein, relative to the amount of active agent in the loaded device, about 7 to 80% by weight of the active agent is removed from the device during extraction step a). 18. A method for releasing an active agent solute into an aqueous environment, characterized in that the active agent is released from a device according to claim 1. 19. The method of claim 18, wherein said active agent is a pharmaceutical substance. 20. The method of claim 19, wherein the device is bead-shaped.