JPS6043327B2 - Manufacturing method of drug releaser - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for manufacturing a drug releaser.

Drug release devices (also referred to as truck delivery devices) that provide sustained release of drugs or other active agents are well known in the art. A typical drug release body consists of a shaped body, usually solid, particulate, homogeneously dispersed in a polymeric matrix that is permeable to the drug by diffusion. The polymeric matrix can be substantially non-porous and homogeneous, in which case the drug is dissolved within and permeates through the polymeric material itself. Another type of matrix is microporous, the pores containing a drug-permeable liquid or gel medium, and in which case the drug is preferentially dissolved in the medium within said pores; and permeate through the medium. It is of course also possible to use a polymer matrix formed by a polymer that is microporous and at the same time permeable to drugs, in which case:
The transport of drugs within the matrix is achieved by a combination of the above methods. Releases the active agent into an aqueous environment.

Other types of drug releasers used, for example, to release drugs into various cavities of the human body, are dispersed within a polymeric matrix that is impermeable to the active agent but permeable to water;
and a shaped body of discontinuous particulate osmotic solute-activator depots (storage sites) surrounded by the matrix, such that the cohesive force of the matrix is lower than the pressure generating capacity of each depot. .Such emitters are
Osmotic absorption-ejection mechanism (0sm0ticimbibiti)
0n-BL! r'Sting mechanism). That is, in this case water is osmotically absorbed into the depot close to the outer surface of the emitter, thereby dissolving the contents of the depot and creating a pressure therein, causing the surrounding polymer matrix to disintegrates, releasing the active agent from the matrix and allowing the next closest depot to approach the surrounding environment, such that in turn this occurs. Such a permeable ejector is the subject of Japanese Patent Application No. 49-47092, filed on April 25, 1939, which is hereby incorporated by reference.
Such emitters are attractive products because they are inexpensive and easy to manufacture compared to other types of emitters, such as laminated emitters or encapsulated emitters.

In addition, in the case of certain drugs, such emitters are
It is the only one that can sustainably release drugs at a therapeutically effective rate. However, such release bodies often exhibit unsuitable active agent release kinetics.

That is, the ejection begins at a high rate (referred to as the initial ejection) and this rate quickly decreases to a significantly lower rate. The diffusion dynamics of an emitter with a thin rectangular cross section (i.e. an emitter formed as a flat slab) is described by the following equation. where (M,) is the active agent released during time (t), (Cs) is the solubility of the active agent in the polymer matrix, and (CO) is the total concentration of active agent in the polymer matrix (CO is C8), (D) is the diffusion coefficient of the active agent within the polymer matrix, and (4) is the surface area on both sides of the emitter.

Equations defining release kinetics for other simple shapes such as cylinders and spheres are also well known. Tree 2 (*1) Tea Higuchi (T
．． Higuchi), Journal of Pharmaceutical Science (J.Pharm.Sci.)
, Volume 4, Page 874 (1961) (*2) T.J.Rosemen et al.
Journal of Pharmaceutical Science (J.Pharm.Sci.), Seki Volume, 353 pages (1
97) T.J. ROSEMAN, Journal of Pharmaceutical Science (J.Pharnl.Sci.)
Volume 61, page 46 (197 details) and H.K. Ronsdale, R.W. Baker, ``Controlled Release of Biologically Active Agents'', New York, Plenum Press, C. Tanqller
y) Edit (197 Details) If we plot the snow rate against t in the above equation, the release rate at the initial stage of release is very large and quickly falls to a level significantly lower than the rate at the initial stage.

Corresponding plots for other simple shapes of diffuse emitters, such as rod cylinders or spheres, have release rate patterns similar to the simple slabs described above. Release kinetics have been experimentally determined for osmotic ejectors, but again the initial ejecta rapidly declines in velocity.

For osmotic emitters, the release rate after this initial decrease exhibits a flat curve, whereas for diffuse emitters it decreases continuously. In both types of emitters, it is undesirable for such an initial burst of active agent to occur.

This is because it may result in over-dosing, toxic effects or side effects, or failure to accommodate optimal drug dosing control for a particular active agent.
The initial high level or "spurt" in the release rate of active agent from such emitters can be reduced by coating the body of the emitter with a layer of pure polymeric matrix.

Such coated emitters are described in T.H.Shepherd, May 4, 1927,
d) As described in other U.S. Pat. No. 3,577,51, the coating is used for another purpose. However, this coating method has the disadvantage of reducing the overall release rate profile of the emitter (ie, the overall plot of sparing vs. t). Such a reduction would reduce the required release rate for drug efficacy. Furthermore, if the shape of the emitter is irregular, it is difficult to devise a manufacturing method that can produce a continuous and uniform coating on the emitter in a reproducible manner. be. The present invention includes the steps of forming a dispersion containing solid particulate active agent within a polymeric matrix and forming the resulting dispersion from the previous step into a shaped body suitable for placement in an environment of use. In a method of manufacturing a drug release body, the polymeric matrix is removed by washing the body in a liquid inert to the polymeric matrix to remove solid particles or active agent from the surface of the body. further comprising the additional step of forming a layer emptied of active agent such that the thickness of the layer is at least 5% of the overall thickness of the body.

FIG. 1 shows a disc-shaped diffusible active agent release body. This emitter, generally designated by 10, includes a particulate active agent 11 such as a drug dispersed within a polymeric matrix 12.
It is composed of. the particles of active agent 11 are liquid;
It can be semi-solid or solid, but preferably solid. As used herein, the term "active agent" refers to a composition which, when placed in an environment of use, produces the desired beneficial and useful results.

Such active agents include, for example, insecticides, herbicides, fungicides, algaecides, rodenticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, surfactants, disinfectants, catalysts. , fermentation agents, nutrients, medicines, plant minerals, evacuation agents, plant hormones, air purifiers, microbial inhibitors, etc. As used herein, the term "drug" is a physiologically or pharmacologically active substance that produces local effects at the site of administration or systemic effects at sites remote from said site of administration. Substances. Such drugs include inorganic and organic compounds and include drugs that act on the central nervous system, such as hypnotics and sedatives, stimulants, tranquilizers, anticonvulsants, muscle relaxants and antiseptics. Parkinson's disease agents, antipyretics and anti-inflammatory agents, local anesthetics, chain spasm agents and anti-inflammatory agents, vasodilators, microbial inhibitors, hormonal agents, estrogen steroids, progesterone steroids, sympathetic nerve stabilizers, cardiovascular agents, diuretics, anthelmintics,
There are hypoglycemia treatment agents and eye drops. In an osmotically ejected release device, the active agent is soluble in water to the extent that the osmotic pressure of its saturated solution exceeds the osmotic pressure of the external use environment, or it contains an inorganic or organic salt capable of generating such osmotic properties. It must be compatible with compatible solutes that have osmotic effects, such as:

Such pressure provides the necessary driving force to operate the seepage jet mechanism. Methods for calculating and measuring osmotic pressure are well known. Regarding this point, for example, published by Misaki London in the 3rd Showa period, published by Matsuku Millan, and published by S.Gl.
Asst On), "Physical Chemistry Themist Blog" As mentioned above, in a diffusive emitter, the polymer forming the polymer matrix is substantially non-porous and homogeneous. or microporous.

Such polymers and matrices are disclosed in Japanese Patent Application No. 47-98573 (Japanese Patent Publication No. 55-412) filed by the present applicant.
No. 06), and examples include the following: poly(methyl methacrylate), poly(butyl methacrylate), ethylene-vinyl acetate copolymer, vinylidene chloride-acrylonitrile copolymer, vinyl chloride-
Diethyl fumarate copolymer, silicone rubber, acrylonitrile-diotiglycidol copolymer, acrylonitrile-ethylene oxide copolymer. Further, the polymer for forming the second type of osmotic ejector is disclosed in Japanese Patent Application No. 49-470 filed by the present applicant.
-19291) and include, for example: celluloses such as commercially available non-plasticized and plasticized cellulose acetate, hydroxylated and non-hydroxylated ethylene-vinyl acetate copolymers.

In a diffusive emitter according to the invention, the concentration of active agent dispersed within the polymer matrix is determined in principle by the desired dosage level for the emitter.

The concentration of the active agent is usually 5-
It is within the range of 70% by weight. Its particle size is usually 0.1
-100 microns. In osmotic ejectors, the degree of loading of the active agent within the depot (storage site), which depends on the size and number of the depots, is important.

The depot typically accounts for 5-7% of the weight of the emitter. In this range, the amount of polymer is sufficient to adequately surround the depot and maintain the original shape of the release body even after a substantial amount of drug has been released. The diameter of the depot is usually in the range of 0.1-100 microns. The shape of the release body formed by the active agent monopolymer dispersion described above will depend on the intended use.

In most circumstances, complex shapes are not required, and it is therefore more convenient and economical for the emitter to have a simple shape, such as a flat disc, cylindrical rod, or sphere. be. In certain embodiments for use in the eye to release the contained eye drops, the release body is usually flat disk-shaped, oval-shaped,
Made into oval or bean-shaped shapes. The size of the emitter will depend on the environment and the required dosage.

Drug release bodies for bodily implantation are sized by the size of the implantation site. For example, in the case of an ocular insert emitter for insertion into a blind canal, its dimensions are 4-20T in length.
f1m1 width is 1-15 order, thickness is 0.1-4T0n, and usually contains 1-200 milligrams of eye drops. The active agent monopolymer dispersion can be formed by mixing the two components by conventional techniques.

Similarly, this dispersion can be prepared by solution casting, extrusion, roll milling,
The shaped body can be formed by conventional techniques such as melt pressing, cutting, stamping, etc. After the dispersion has been formed into the desired form, which may be a final form for introduction into the use environment, or an intermediate form such as a large sheet or roll, it is placed in the use environment. Before I put it down, here's the main thing. The particles of active agent are removed from the outer layer of the body of the dispersion according to the method of the present invention.

This is accomplished by washing the body of the dispersion using a liquid that is inert to the polymer matrix. In other words, the liquid dissolves, decomposes or dissolves,
It must not have a harmful effect on the polymer matrix through chemical reactions with Tuxus. It is convenient and economical to use an aqueous liquid as the cleaning liquid, and water is preferred. In a diffusive emitter, washing the emitter disperses the active agent dissolved on the surface of the polymer matrix into a washing liquid, which in turn dissipates the active agent closer to the surface. The active agent particles are dissolved within the polymer and diffused out of the polymer.

In the case of osmotic ejectors, the washing dissolves the active agent located on the surface, and the water absorbed by the surrounded active agent depot ruptures it. Allow the contents to be released. In both types of emitters, this washing results in a surface layer of the desired thickness that is ultimately free of active agent. In the case of the emitter shown in FIGS. 1 and 2, the drug is completely evacuated from the layer designated as (4), leaving a void 14 on the outer surface of the emitter. . The number and size of these cavities within the matrix depends on the concentration of dispersed active agent and the size of the particles. In this regard, if the emitter is dried after washing, these cavities irreversibly shrink. That is, it has been found that the porosity of the layer is reduced. It is believed that this phenomenon causes the dried emitter layer to act as if it were a pure matrix coating. The reason is that said layer is less permeable to the active agent than the remaining parts of the matrix. In any case, the cavity 14 influences the release kinetics on the emitter 10 since it forms a suitable path (indicated by the small arrow) along which the active agent diffuses. Figures 7 and 8 illustrate an osmotically ejected active agent releaser.

This emitter, designated in its entirety by 15, has been previously washed with water according to the method of the invention. Main emitter 1
5 has discontinuous active agent monoosmotic solute depots 16 encapsulated within a polymeric matrix 17. As shown in FIG. 8, the prewash completely drains the active agent depot from the surface layer (B), leaving a void 18. This cavity 18 is similar to the cavity 14 of the emitter 10, except that it is substantially interconnected due to the ejection mechanism when the active agent is released. The conditions under which the washing is carried out, such as time and temperature, are selected such that the thickness of the layer from which the active agent is removed is a predetermined value.

Given the desired thickness of the layer, the temperature and time of washing will depend on the particular polymer and active agent used. In diffusive emitters, cleaning times can be reduced by using temperatures that promote diffusion. In osmotic emitters, cleaning times can be reduced by using temperatures that enhance moisture uptake by the deposit. In almost all cases, washing time will be reduced by using elevated temperatures (above ambient temperature) that are below the melting temperature of the matrix and below temperatures that would adversely affect the active agent. For most polymers and active agents, 50
Washing temperatures in the range -60°C are preferred. For the above two types of emitters, washing is carried out with stirring,
It is desirable to ensure removal of the active agent released from outside the emitter. Regardless of the degree of washing, prewashing can improve the release kinetics of the emitter;
at least 5% of the overall thickness or diameter of the emitter;
It is desirable to remove the active agent from comparable layers.

The thickness of this layer is typically about 5-25% of the overall thickness or diameter of the emitter. It is to be understood that in most emitters this layer is present on both sides or edges of the emitter and the percentages above are for only one of the layers. In other words, in the case of a spherical emitter, said layer is located at each end of one diameter, so that the entire diametrical portion of the emitter that is completely evacuated of drug is at least about the diameter of the emitter. It is 10%. The method of the invention and the improvements achieved by it in release kinetics are illustrated by the following examples.

Example 1 (4) Expansion used to deliver drugs into the uterus! Dispersible emitters were formed by mixing nodular progesterone (particle size 5-10 microns) in a methylene chloride solution containing 80% ethylene-vinyl acetate copolymer (drug loading approximately 20 microns). capacity%).

This mixture was cast to form a sheet with a thickness of 0.2 cm, and a rectangular body having a total surface area of 1 c1t was cut from this sheet. The rectangular body was placed in a simulated uterine environment, allowing progesterone to be released by diffusion. FIG. 3 shows the monitoring of this release state and plotting its progress. As shown in this figure, the initial release rate of progesterone is about 150 pda per day, and this rate rapidly decreases to about 40 μy/day for the first 100 days, after which the release curve becomes gradual.
Continuously descends until solid progesterone is exhausted.
B) Three rectangular bodies were formed from the progesterone-ethylene-vinyl acetate dispersion in the same manner as in (4).

Each rectangle was washed with 50 g of water. The first rectangular body has a thickness of 0
．． 02CrIL until a chemical-free surface layer is formed.
The rectangular body was washed until a chemical-free layer with a thickness of 0.033α was formed, and the third rectangular body was washed until a chemical-free layer with a thickness of 0.047c7n was formed. Then each emitter (
As in case 4), the mice were placed in a simulated uterine environment, and the release of progesterone was monitored and its progress plotted. Fourth
The figure shows the curve at this time. As evidenced by these curves, the initial release rates of the washed release relative to the unwashed release are approximately 30%, 60%, and 70% reduced, respectively.
Also, the main period of the emitter's life (approximately 100-500 days)
The release rate was not significantly reduced by washing. ? Example 2 - One emitter similar to Example 1A, and two other emitters similar to 1A except for drug loading (one containing half the amount of progestin and one containing 2 (containing twice the amount of progesterone) was formed and tested as in Example 1A.

A plot of the release course is shown in FIG. () Three types of emitters were formed in the same manner as in (4) above, and each was washed in advance with water at 50° C. until a chemical-free layer with a thickness of 0.047 Crf1 was formed.

These emitters were then tested as in Example 1A. A plot of the release course is shown in FIG. As can be seen by comparing Figures 5 and 6, although the initial burst of progesterone release is eliminated by washing, there is no significant effect on the release rate over most of the life of each emitter. The impact is not very noticeable.

3 Example 3 An osmotic ejector, such as that used to deliver drugs to the eye, was prepared by mixing part pilocarpine nitrate and part D of ethylene-vinyl acetate copolymer with a laboratory rubber roller. It was formed.

This well-dispersed mixture containing pilocarpine nitrate particles with an average diameter of 1-10 microns was formed into a flat film 500 microns thick by pressing, and from this sheet a major diameter of 13.5 Tr! Inl short diameter 6.57r
r! n ellipsoids were cut.

The elliptical body was placed in a simulated tear fluid, allowing pilocarpine nitrate to be released by an osmotic-jet mechanism. This release progress was monitored and plotted in FIG. 9. As shown in this figure, the initial pilocarpine nitrate release rate is approximately 175 μf/hour, and the initial 2? During this period, it rapidly decreases to 25 μy/hour. (B) The same five emitters as in the previous case were formed and each emitter was immersed in 35°C water for 15, 30, 60, 12 times and 2 times, respectively.

Each emitter was then tested in the same manner as in (4). FIG. 10 is a plot of the release progress of pilocarpine. As shown by these curves, the washings reduced the initial release rate by 20%, 40%, 50%, and 90%, respectively.
lower. Moreover, after 2 hours, there is almost no difference between the washed emitter and the unwashed emitter. Example 4 Using a rubber roller, the tetracycline hydrochloride of the nod was dispersed in 70 parts of ethylene-vinyl acetate copolymer (Elvax22O), and the dispersion was melt-pressed into a flat film of 500 microns thick. In addition, by forming it into an elliptical shape with a major axis of 13.3 TWL1 and a minor axis of 5.8, an osmotic ejection type ejector for insertion into the eyeball was formed.

Each ellipsoid was soaked in water at 50°C for 0, 15, 30, and 6 hours, respectively.
Washed for 0 and 120 minutes and placed in simulated tear fluid after drying. The average release rates of tetracycline hydrochloride during the first 7 hours were 1 & 17, 12 and 9 μfl/hr, respectively. Example 5 An insert emitter was formed and tested as in Example 4, except that a different type of ethylene-vinyl acetate copolymer (Elvax4O) was used.

The average release rates of tetracycline hydrochloride during the first 7 hours were 25s1\12, 9 and 6 μg/hour, respectively. Preferred embodiments of the present invention are as follows.

(1) A method according to the claims, wherein the liquid is water.

(2) The method of paragraph (1) above, wherein the emitter is a diffusive emitter and the washing is performed at an elevated temperature to enhance diffusion of the active agent from the matrix. .

(3) The method described in any one of (1) to (2) above, wherein the polymer matrix is an ethylene-vinyl acetate copolymer, and the washing is carried out at a temperature of 50 to 60°C.

(4) In the method described in any one of (1) and (3) above, the emitter is an osmotic ejector,
and a method of washing at an elevated temperature such that the liquid is enriched with the active agent.

(5) A method as claimed in the claims and any one of (1) to (4) above, in which the thickness of the layer is approximately 5 to 25% of the overall thickness of the body. (6) A method using a drug as an active agent in the method described in the claims and any one of (1) to (5) above.

[Brief explanation of drawings]

FIG. 1 is a vertical sectional view of a disc-shaped diffusive drug emitter formed by the method of the present invention. FIG. 2 is an enlarged view of a portion of the emitter shown in FIG. 1 taken along line 2--2 in FIG.
FIG. 3 is a graph showing the release kinetics of a diffusive drug releaser according to the prior art. FIG. 4 is a graph illustrating the improvement in release kinetics obtained when the emitter of FIG. 3 is subjected to the method of the present invention. FIG. 5 is a graph showing the release kinetics of several prior art emitters having the same geometry as the emitter in FIG. 3, but with different active agent loadings. There is. FIG. 6 is a graph illustrating the improvement in release kinetics obtained when the emitter of FIG. 5 is subjected to the method of the present invention. FIG. 7 is a vertical cross-sectional view of a disk-shaped seepage-jet emitter formed by the method of the present invention. FIG. 8 is an enlarged view of a portion of the emitter shown in FIG. 7, taken along line 8--8 of FIG. FIG. 9 is a graph showing the release kinetics of a prior art osmotic ejector. FIG. 10 is a graph illustrating the improvement in release kinetics obtained when the emitter of FIG. 9 is treated by the method of the present invention. In the figure, 10 is a disc-shaped diffusive active agent releaser, 11 is a particulate active agent, 12 is a polymer matrix, 14 is a cavity, 15 is a disc-shaped osmotic-jet active agent releaser, and 16 is an injectable active agent releaser. continuous active drug one osmotic solute depot, one
7 is a polymer matrix and 18 is a void.

Claims (1)

[Claims] 1. Drug release comprising forming a dispersion containing a solid powdered active agent within a polymeric matrix and forming the dispersion obtained in the previous step into a shaped body suitable for placement in an environment of use. In a method of manufacturing a body, a polymer matrix is loaded with active agent by washing the body in a liquid that is inert to the polymer matrix to remove the solid particulate active agent from the surface of the body. A method of manufacturing a drug release body, comprising the additional step of forming an empty layer such that the thickness of the layer is at least 5% of the total thickness of the body.