JPS59225112A - Slow-releasing composite and its production - Google Patents

Abstract

PURPOSE:To obtain a slow-releasing drug for embedding, by compression molding pyroglutamylhistidyltryptophylseryltyrosyl-D-leucyl-leucylarginylproli neethyl amide in a proper form, and including the formed product in a polymer. CONSTITUTION:The above compound or its salt expected to have a remedying effect to the hormone-dependent human mammary cancer or prostatic cancer, is compression molded to a proper form under a pressure of 100-1,000kg/cm<2>, usually 100-600kg/cm<2>. One or more formed products are laminated, coated with a mixture of glass-forming monomers, and irradiated with light or ionizing radiation at room temperature--200 deg.C to obtain a slow-releasing composite without deactivating the above active component. The monomer is those resistant to crystallization at low temperature, and capable of forming a stable supercooled state or glassy state easily and keeping its polymerization activity.

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention The present invention provides a sustained release complex containing pyroglutamyl histidyl tryptophyllseryl tyrosyl-D-leucyl leucyl arginyl proline ethylamide or a salt thereof, and a method for producing the same. Regarding.

Pyroglutamyl histidyl tryptophyllseryl tyrosyl-〇-leucyl leucyl arginyl proline ethylamide or its salt (acetate hereinafter referred to as "TAP-144")
(sometimes abbreviated as ) is LH-R1 ((luteinizing hormol-releasing hormone (lu)
m, one-releasing h, ormone)
'] It was screened as a derivative with stronger activity than natural LH-RH through derivative synthesis research, and has the following structural formula; -Pro-NHG2
H5 (Engineering UPAC-Engineering UB Cromission
one Biologica, l Nom, encla, tu,
(abbreviation by re) The compound can be converted into a salt by reacting with a suitable acid. These acids include, for example, hydrohalic acids (e.g. hydrochloric acid or hydrobromic acid), perchloric acid, nitric acid, sulfuric acid, phosphoric acid or organic acids such as formic acid, acetic acid, propionic acid, lactic acid, anhydrous fudocic acid, Shiyupentaic acid, malonic acid, cono-phosphoric acid, maleic acid,
Examples include fumaric acid and sulfanilic acid. The following TA
Explanation 1 using P-144 as an example.

When TAP-1i is repeatedly administered to animals, serum LH,
FSH is reduced and may even inhibit the development of male and female reproductive organs. As described above, in female rats, 7,12-dimethyl has an inhibitory effect on ovarian growth, and 7,12-dimethyl has an inhibitory effect on breast cancer induced by 7,12-dimethyl, which is expected to have a therapeutic effect on hormone-dependent human breast cancer.
In addition, in male rats, there was a marked decrease in the weight of the penis, prostate gland, and other secondary reproductive organs, a marked decrease in serum testosterone, and growth inhibition of transplanted rat prostate cancer, indicating that the therapeutic effect on human prostate cancer is not effective. There are high hopes for this, and intensive research is currently underway.

Incidentally, TAP-144 is water-soluble and is stable in an aqueous solution at room temperature for at least one year. TAP-144 is
In order to have a pharmacological effect, it is administered by subcutaneous injection every day, but patients experience too much negative phase.

As a result of intensive research into an administration method that maintains the pharmacological effects of TAP-144 and reduces the burden on patients as much as possible, the present inventors have determined that TAP-144 can be manufactured in a sustained-release implantable manner. The present invention was completed after discovering that one of the desired objectives could be achieved.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a sustained release complex containing TAP-144 and a method for producing the same.

Another object of the invention is to provide at least one or one layer of TA.
The object of the present invention is to provide a sustained release composite containing P-144 in a vinyl polymer matrix.

A further object of the present invention is to stack at least one or one layer of TA or P-144 molded into an appropriate shape under appropriate pressure and surround it with one or more vinyl polymerizable monomers. After enveloping it in the body, TAP-1 is produced by irradiating it with light, military, or releasing radiation at low temperatures to polymerize the nitride-capable monomer.
The object of the present invention is to provide a method for producing a sustained release composite comprising encapsulating 44 in a vinyl polymer.

Still another object of the present invention is to stack a small number of TAP-144 molded into a suitable shape under suitable pressure (at least one piece or one layer), and filler (material) at desired positions in the middle and above and below. The surrounding area is surrounded by one or more types of vinyl polymerizable monomers, and then the vinyl polymerizable monomers are polymerized by irradiation with light or ionizing radiation at low temperatures to form a filling material. An object of the present invention is to provide a method for producing a sustained release composite comprising TAP-144 laminated between layers.

Other objects and advantages of the invention will become apparent below in conjunction with the accompanying drawings.

In accordance with the present invention, at least one pyroglutamyl histidyl drift filceryl tyrosyl-D-leucyl leucyl arginyl proline ethylamide or compression molded thereof into a suitable shape is laminated and, if desired, After placing a filler (material) of an appropriate shape in the desired position between them and/or above and below, one or more fillers (materials) that do not crystallize even at low temperatures and easily form a stable supercooled state or glass state are used. The polymerizable monomer or the polymerizable monomer itself is in a supercooled state at low temperatures (・does not form a glass state; ・coexists with the polymerizable monomer to form a polymer at low temperatures Pyroglutamyl histidyl trypto is produced by polymerizing the polymerizable monomers by irradiating them with light or ionizing radiation at a temperature range of room temperature to -2'00°C. A sustained release complex incorporating filseryl tyrosyl-D-leucyl leucyl arginyl proline ethylamide has been prepared.

The pressure applied to compression mold TAP-144 under pressure according to the present invention is between 100 and 100 oo.

A range of K5'/cm2 is appropriate, but usually 10
The pressure in the range 0-60 D Kg/cm2 can be selected depending on the desired shape. The shape to be molded is appropriately selected depending on the mode of use of the sustained-release composite, such as tablet, film, granule, disc, needle, or rectangle. Possible ways to use the composite of the present invention include surgically implanting it into the affected area, applying it directly to the affected area with a syringe, etc.

TAP-1 compression molded into a suitable shape according to the present invention
44 (hereinafter sometimes abbreviated as "□Compressed TAP-144") are stacked in at least one or one suitable container.In this case, when using multiple compressed TAP-144 are stacked at appropriate intervals from each other.After stacking one or more compressed TAP-144 in a container, one or more vinyl-based polymerizable monomers are injected to form one or more compressed TAP-144. -144 is completely encapsulated.

When stacking compressed TA"P-1i in a container, if a single compressed TAP-144 is used, above and below it,
If multiple compression TAP-144s are used, each compression TA
By interposing fillers between and above and below the P-144, the rate of elution from the final complex can be controlled.

In producing sustained release complexes in accordance with the present invention, it is necessary to perform processing operations to keep the initial elution rate of TAP-144 from the final complex low. For this purpose, the inventors have discovered the treatment method described below.

(b) When one side of the compressed TAP-144 is placed in close contact with the bottom of the composite, the layer of lt-terminus small coalescence at the top of the composite is thicker than the TAP-144, so TAP-1 from the top
Elution of 44 takes time. Therefore, the elution of TAP-144 from the bottom surface of the complex becomes rate-limiting. In the case of this form of complex, TAP-144
The elution rate can be controlled to a certain degree.

(b) When compressed TAP-144 is placed in close contact with both surfaces of the polymer: Elution from the upper and lower surfaces of the composite becomes rate-determining.

(c) By interposing a filler above, below, or in the middle of compressed TAP-144, the polymer surface and compressed TA
By appropriately controlling the distance to the P-144 surface, the elution of TAP-144 from the complex in the early stage can be reduced.
It can be kept in check. As mentioned above, the early stage elution of TAP-144 from the complex can be controlled by physical processing such as the position of compressed TAP-144 within the complex or the presence of a filler. , the hydrophilicity, porosity, adsorption properties, etc. of the polymer can be adjusted over a wide range.

In the present invention, the amount of TAP-1zM included in the complex is appropriately determined depending on the purpose of use of the complex, the shape of the complex, etc.

TAP-144, which is included in the present invention, is hardly compatible with many polymeric substances (in addition, it is unstable and easily decomposes and deactivates at high temperatures. Therefore, it is a polymerizable monomer that can be polymerized at low temperatures. One of the structural features of the present invention is to select TAP-144 as a carrier.As a method for polymerizing at low temperature, light or ionizing radiation with extremely low activation energy for the initiation reaction is used. It has been well known that the polymerization method is advantageous.Ordinary polymerizable monomers tend to crystallize at low temperatures, and in the crystallized state at low temperatures, molecular movement is restricted and the growth reaction rate is extremely low. Because of the small size, they usually lose their polymerizability or only obtain an extremely low polymerization rate.Therefore, methods such as simply cooling the polymerizable monomer and polymerizing it at a low temperature will reduce the polymerization rate. Increasing the temperature and controlling the offshore temperature are incompatible, and it is difficult to achieve both at the same time.

As a result of intensive research, the present inventors have discovered that by using a specific polymerizable monomer, it is possible to simultaneously achieve the objectives of increasing the polymerization rate and controlling the polymerization temperature, and have arrived at the present invention.

That is, unlike ordinary polymerizable monomers, the polymerizable monomer that includes compressed TAP-144 according to the present invention has a special molecular structure and physical properties, and therefore does not crystallize easily at low temperatures. It is a so-called vitrifying monomer, which forms a stable supercooled state or glassy state without losing its polymerizability. Polymerization of vitrifying monomers in a supercooled state can be called solid phase polymerization in an amorphous state, and since the polymerizability is high in a low temperature region, it is possible to use bioactive substances that are easily deactivated by heat. It is an extremely useful means for applications such as immobilization and sustained release. Suitable examples of such polymerizable monomers include; ethylene dimethacrylate;
Diethylene glycol dimethacrylate, diethylene glycol diacrylate-1, triethylene glycol dimethacrylate-1, triethylene glycol diacrylate, tetraethylene glycol dimethacrylate, tetraethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, Diethylamine ethyl dimethacrylate, glycidyl methacrylate, epoxy acrylate, glycidyl acrylate-1, hydroxybutyl acrylate, hydroxyethyl acrylate, hibiroxyprogyl methacrylate, hydroxypropyl acrylate, hydroxybutyl methacrylate, hydroxybutyl acrylate, hydroxyhexyl methacrylate,
Hydroxyhexyl acrylate, butanediol dimethacrylate, butanediol diacrylate, propanediol dimethacrylate, propanediol diacrylate, bentanediol dimethacrylate, deep tanediol diacrylate, hexanediol dimethacrylate, hexanediol diacrylate, neopentyl glycol dimethacrylate , neopentyl glycol diacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trimethylolethane triacrylate, trimethylolethane trimethacrylate, polypropylene glycol diacrylate, polypropylene glycol dimethacrylate, glycerol monomethacrylate unsaturated polyester Examples include.

However, in the present invention, in addition to the above-mentioned vitrifying monomers, it is possible to use a vitrifying monomer that is in a supercooled state or does not form a glassy state at low temperatures, but is mixed with the vitrifying monomer in a certain composition range. Thus, one or more polymerizable monomers that can be polymerized as a whole at low temperatures may also be used. Such polymerizable monomers include acrylic acid, methacrylic acid, vinylpyrrolidone, acrylamide, methacrylamide, vinyl acetate, vinyl propionate, vinylopestylene acetate, hinyltoluene, cyhinylbenzene, methyl methacrylate, ethyl methacrylate, propinope methacrylate. Butynope methacrylate Intinope methacrylate Hexyl methacrylate, octyl methacrylate, lauryl methacrylate, methacrylic acid (endil, cyclohexyl methacrylate, stearyl methacrylate, metinope acrylate, butyl acrylate, ethyl acrylate, maleic anhydride, etc.) For example, these polymerizable monomers may be used in an amount not exceeding 40% of the total amount of polymerizable monomers.

When carrying out the present invention, the quantitative ratio of TPA-144 and the polymerizable monomer is appropriately determined depending on the size, shape, purpose of use, desired properties, etc. of the composite.
In the case of TAP-144 with a weight of ioomp compressed into a tablet with a thickness of 0.5 to 07 mm and a thickness of 085 to I CC
of polymerizable monomers are used.

In the present invention, the elution of TAP-144 from the complex can also be controlled by allowing the crystalline component to coexist with the above-mentioned polymerizable monomer.

Such crystalline components include water, dioxane, ethylene glycol, polyethylene glycol, cyclohexane, benzene, acetic acid, propionic acid, butyric acid, urea, carotonic acid, maleic acid, malic acid, succinic acid, sorbic acid,
Itaconic acid, 7L-decane, n-menane, ruhexane, ruhebutane, paraffin, stearic acid, palmitic acid, lauryl alcohol, octyl alcohol, caffrylic acid, caproic acid, capric acid, stearyl alcohol, palmityl alcohol, methyl stearate , methyl stearate, methyl acetate, ethyl acetate, methyl acetate, propyl acetate, propionamide and the like.

According to the present invention, compressed TAP-144 is encapsulated in one or more of the above-mentioned polymerizable monomers, and then
A sustained release composite is produced by polymerizing the polymerizable monomer by irradiating it with light or ionizing radiation at a temperature range of 00'C;

Radiation sources employed in carrying out the present invention include visible ultraviolet light from low-pressure or high-pressure mercury lamps, sunlight, light from photon factories, X-rays, gamma rays, beta rays, electron beams, alpha rays, and chemical nuclear reactors. It can be either mixed radiation from radiation, gamma rays from solar fuel or fusion products. For ionizing radiation, the dose rate I x 10
A radiation dose of 1X10' to 5x106R1, preferably 1X10'' to 1X106R at ~1x109R/h is required.

In the present invention, when a single compressed TAP-144 is enclosed, a suitable filler is added to at least one side thereof, and when a plurality of compressed TAP-144 are enclosed, an appropriate filler is added between them and/or on their upper and lower surfaces. It also includes an embodiment in which the elution of TAP-144 in the initial stage of the complex is controlled as desired by mixing the filler (material). These fillers are appropriately selected from substances that do not have a negative effect on the living body even if left in the body. Examples of these fillers include gelatin, heat-denatured proteins, polylactide, and polyamino acids. biodegradable polymers, general synthetic polymers,
It is in the form of cloth, membrane, nonwoven fabric, fiber, etc. made of glass fiber, paraffin, filter paper, natural fiber, etc.

The present invention will be explained in more detail with reference to Examples below. In addition, the size of TAP-144 from the composite in the examples
The tro elution test was conducted at 67°C using 0.1M IJ acid buffer (PH7,4) as the elution medium.

Examples 1-2 TAP-144200In';) at 400Kj9/cm
It was compression-molded into a flat-bottomed plate shape with a diameter of 11 mm at a pressure of

After placing this flat-bottomed plate-shaped TAP-144 in the center of the bottom of a flat-bottomed glass ampoule with an inner diameter of 151 m, a polymerizable monomer consisting of 80% diethylene glycol dimethacrylate and 20% polyethylene glycol #600 dimethacrylate was added. 0.4 ml of the body mixture (
Example 1) and 1.0 ml (Example 1) After injection, the vaginal ampoule was sealed at 10-3 mmHg. Then,
The ampoule is heated to 178 cm using Tri-I-ethanol refrigerant.
After cooling to 0.degree. C., the monomers were polymerized by irradiation with gamma rays from a cobalt-60 source at a dose rate of 5.times.10.sup.5 gamma ad/hour for 2 hours to prepare a sustained release composite. The elution rate of T'Ap-144 at υitγ0 from these two types of abdominal combinations is shown in FIG. In the figure K) and (top) correspond to Examples 1 and 2, respectively.

Examples 6 to 4 Except for using 0.4 ml of 2-hydroxyethyl methacrylate (Example 4) and 0.4 ml of trimethylolpropane trimethacrylate (Example 4) as polymerizable monomers in Example 1. All experiments were repeated under the same conditions to produce sustained-release composites. The elution rate of TAP-144 from this complex is shown in FIG. 2 (corresponding to Example B) and FIG. 6 (corresponding to Example 4).

Example 5 The experiment conducted in Example 2 using five pieces of TAP-144 compressed at °C was repeated to obtain a flat-bottom disk-shaped TAP with a diameter of 11 mm.
A sustained release complex containing five -144 molecules was prepared. TAP-144 from this complex vif:ro
Figure 4 shows the elution rate of TAP-'144.

Example 6 TAP-144 oomp was compression molded into a flat-bottom disk shape with a diameter of 11 mm at a pressure of 500 K97 cm2. This flat-bottomed disk-shaped TAP-144 was placed in a glass ampoule with an inner diameter of 16+o+. In this case, the top and bottom of TAP-144 were filled with glass fibers of 1 thickness and 11 diameters. Thereafter, Q, 5 ml of a polymerizable monomer mixture consisting of 70% neopentyl dalicol dimethacrylate and 30% methoxypolyethylene glycol #1000 methacrylate was poured into this ampoule, and the polymerization conditions were the same as in Example 1. Polymerization was performed to produce a filled composite. inυitγ of TAP-144 from this complex.
The elution rate in O is shown in FIG.

Examples 7 to 10 Pressure 100 K9/cyn2 as filler (material),
A human-derived γ-globulin membrane (Example 7), a gelatin membrane (Example 8), a pharmacopoeial gauze (Example 9), and a Mirafin paper (Example 10) obtained by treating at a temperature of 90°C for 4 seconds.
) A composite was produced under the same conditions as in Example 6, except that the same conditions as in Example 6 were used. ic of TAP-144 from the complex
The elution rate at yυitγ0 is shown in FIG. ○ in 5 diagrams
, 口, △, O, and Kaku correspond to the results of Examples 6 to 10, respectively.

Example 11 TAP-1441g was compression molded into a 4 am, x 4 cm film at 600 K and a pressure of 9/am2. This film-like TAP-144 is placed in a glass container, and EPTFE manufactured by Japan Goatenox Co., Ltd. is placed above and below it.
, ξ Tsuchi (4 cm, X 4 cm, After injection, the container was sealed. Next, the contents in the container were solidified with liquid nitrogen at -24°C using carbon tetrachloride as a cryogen, and then exposed to gamma rays from a cobalt-60 radiation source at a dose rate of 5 x 105 rad/hour in a nitrogen atmosphere. The polymerizable monomer was polymerized by irradiation for a period of time to produce a highly flexible membrane-like composite.

i1zυ from this first combination! , TAP in lrO
The elution rate of -144 is shown in FIG.

Examples 12-1 200 mg of TAP-144 was compression molded into a flat-bottomed plate shape with a diameter of 11 mm at a pressure of 400 to 9 cm2. After placing this flat-bottomed plate-shaped TAP-144 at the center of the bottom of a flat-bottomed glass ampoule with an inner diameter of 15m7π,
80% diethylene glycol dimethacrylate and 2
Polymerizable consisting of 0% polyethylene glycol #600 dimethacrylate, 11. mass mixture k (13.4ml
(Example 12) and 1.0 ml (Example 1)
The injected hindlimb ampoule was sealed with 'I 0-3 mm, H&. The ampoule was then rapidly cooled to -60°C. Thereafter, the mixture was maintained at this temperature and irradiated with light from a high-pressure mercury lamp for 120 minutes to polymerize, thereby producing a sustained-release composite. TA at nυ1tro from this binary complex
Examples 1 and 2 where the elution behavior of P-144 was tested
The results were very similar to the elution behavior of the composite prepared in .

[Brief explanation of drawings]

Figures 1 to 6 show inυ1tr from the sustained release complex of the present invention.
FIG. 2 is a graph showing the elution rate of TAP-17!14 at Patent applicant: Japan Atomic Energy Research Institute (2 others) (4 others) Acceptance / Zuho 2 Figure 0 / 2 3 4 5 g 7
a9 io//molten time I (Japanese milk eye diagram, 4 Figure 5 each appearance v! r dark seal) #5 (2) also 4 Figure 7 each Ryo Ginshu (Japanese) Continuation of page 1 0 shots Name: Shiraishima 1-15-44 Sekimachi, Nerima-ku, Tokyo ■Applicant: Takeda Pharmaceutical Company Limited 2-27 Doshomachi, Higashi-ku, Osaka ■Applicant: Keizo Shida 3-38-27 Showacho, Maebashi City

Claims (1)

[Scope of Claims] 1. A polymer obtained by laminating at least one compression molded pyroglutamyl histidyl tryptophyllseryl tyrosyl-D-leucyl leucyl arginyl zololine ethylamide or a salt thereof into an appropriate shape. sustained release complex. 2. Laminate at least one compression-molded product of pyroglutamyl histidyl tryptophyllseryl tyrosyl-D-leucyl leucyl arginyl zololine ethylamide or its salt into a suitable shape, and 4. If desired, After placing a filler (material) of an appropriate shape at the desired position in the middle and/or above and below, one or more polymers that do not crystallize even at low temperatures and easily form a stable supercooled state or glass state. or a polymerizable monomer that does not form a supercooled state or a glass state with the polymerizable monomer at low temperatures, but coexists with the polymerizable monomer to form a polymer at low temperatures. A method for producing a sustained-release complex that can contain light or electrolyceryl tyrosyl-D-leucyl leucylarginyl proline ethylamide or a salt thereof in a temperature range from room temperature to -200°C by enclosing it in a mixture consisting of more than one type. . 3. Pyroglutamyl histidyl tryptophyllseryl tyrosyl-D-leucyl leucyl arginyl proline ethylamide or a salt thereof in a concentration of 100 to 1000 2/Cn
The composite according to claim 1, which is compression molded into a suitable shape under a pressure of 12 degrees. 4. Pyroglutamyl histidyl tricitophyl seryl tyrosyl-D-leucyl leucyl arginyl proline ethylamide or its salt is 100 to 1000 K9/
The method according to claim 2, wherein the product is compression molded into a suitable shape under pressure of CrrL2. 5. The complex according to claim 1 or 6, wherein the salt is an acetate.