CA1125698A - Process for preparing a polymer composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to a process for preparing a polymer composition containing a physiologically active substance.
The process is characterized by contacting one or more polymer-izable monomers and the physiologically active substance, forming them into a specific shape and irradiating the shape with light or an ionizing radiation at a low temperature below room temperature to polymerize the polymerizable monomers. The polymer is a highly desirable material for use as a supporting carrier and allows for the release of the active substance in a controlled manner. The process of this invention allows the active substance to be carried in the carrier in a uniform amount and to be released therefrom at an appropriate rate. The structure of the polymer is such to allow for this release and the active substance may be carried by the polymer at a low temperature to prevent un-desirable side-effects.

Description

BACK5ROUND 0~ THE IN~TENTIoN
The present inventlon relates to a process for pre-paring a polymer composition containing a physiologically active substance. More particularly, the present invention relates to a process for preparing a polymer composition con-taining a physiologically active substance and having a function of releasing the active substance at the controlled rate, In one aspect, the present invention relates to a process for preparing a polymer co~position containing a physio-logically active substance and having a function of eluting theactive substance at the rate controlled by pH.
In another aspect, the present invention relates to a process for preparing a polymer composition comprising a spherical polymer matrix of 50 to 5,000 ~ in size cantaining a physiologically active substance and having a function of !releasing the active subs-tance at the controlled rate.
Various compounds having physiological activities have been broadly utilized in various ~ields including medical science, agriculture and engineering, and these compounds have ~;20 performed their duties indispensably in divergent industrial and domestic applications. Many physiologically active substancesrwhether inorganic substances, organic substances, or substances having high or low molecular weights are known and are now being developed.
-However, in the utilization of these active substances, some common disadvantages have been found.
One disadvantage is that in general these physiologicall~
active substances are effective only within a certain range of concentration in an environment in which they act. They are not only ineffective when in a concentration below such appropriate range but also often bring about harmful side reactions or side .~ ~

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1 effects when in a concentration above the appropriate range. In order to maintain the concentration of such organic substances continuously within the appropriate concentration range, they must be continuously replenished at an appropriate rate as they are consumed or spent through fulfilling their function. Although an apparatus or machine may be used to supply and replenish the desired substances continuously at an appropriate rate a more convenient method is required which can be carried out in any environment and in any place~ One advantageous method to supply and replenish the desired substances is to provide sufficient amounts of the desired substance in a suppoxting carrier whereby the substance may be released from the carrier at the desired rate. A second disadvantage is that many physiologically active substances may deteriorate and decompose due to the environment in which they are maintained or act before they can fulfill their function. Therefore, it is necessary to maintain these active substances in a protected and stable state until their desired function may be fulfilled. In this sense, it is desirable for the efficient utili~ation of the active substances to stabilize ; 2D the substances by maintaining them in an appropriate supporting carrier.
Methods for containing or adsorbing various physiologically active substances in or onto appropriate supporting carriers have ;~ recently been extensively studied. High polymers are high molecular weight compounds. High polymers are one of the more desirable materials for use as supporting carriers. Desired physiologically active substances can be easily caught and maintained within the molecular structure of high polymers and the rate of release of the desired substances can be easily controlled by adjusting the structure and shape of the high polymers by means of polymer B

1 che~ical techni~ues. Further, many of the high polymers are physiologically neutral thereby having no physiological effects on environmentn The problem arises as to how to include or support the desired substance in a high polymer carrier in such a state that the substance can be easily released at a desired rate without reducing the effectiveness of the desired substance Heretofore, high polymer materials used as pharmaceutical additives have generally been polymers such as, for example, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, methyl cellulose, methacrylate-methacrylic acid-methyl methacrylate copolymer, methylacrylate-methacrylic acid copolymer and styrene-maleic acid copolymer. In case of mixing these polymers with medicines to form, for example, a tablet, a large amount of or~
ganic solvent is required to dissolve the polymer. Suita~le or-ganic solvents include chloroform-ethanol, methanol-ethylacetate, cyclohexane, acetone, ethanol, and water. However, traces of these organic solvents other than ethanol and water will remain within the ma-~rix even if the matrix is subjected to a degassing treatment.
. 2~ Whèn medicine is continuously administered over a long period of : . time, side ef~ects due to the cumulative build-up of the organic solvents can become a problem.
A medical preparation which releases an effectlve in-: gredient contained therein (hereinafter referred to as "a control-led releasing agent") may exist in many forms including tablets, films, particles, and powders. In the preparation of such pre-parations from polymerizable monomers, catalysts for polymerization of the monomer, and the medicine, the following disadvantages may ~ arise:
- 3~ (1) To polymerize the monomer the reaction temperature must ,~ , ~23~9~3 1 typically be raised -to near 80C with the disadvantage that the distribution of medicine in -the interior of the resulting matrix may not be uniform and the medicine may be deteriorated bythe high temperature;
~2) Catalyst may remain in the interior of resultant matrix which cannot completely removed; and (3) The costs involved in production of the medical preparation may be high because it can take time periods of up to a few days to complete the necessary reactions.
As one example, it takes 3 days to prepare a controlled releasing agent by polymerizing 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate containing norethandrolene in the presence of t-butylperoctanate as a catalyst under a nitrogen atmosphere at 80C. As another example, a controlled releasing agent may be prepared by polymerizing a polymerizable monomer in the presence of catalyst, impregnating the polymer obtained with a solution containing a medicine to 'permeate the medicine into the interior of the matrix of polymer and then drying the polymer.
F~owever, in the controlled releasing agent so obtained the catalyst is typically not entirely removed from the matrix and dif~iculties ` may be encountered in containing a large amount of medicine per unit volume of the matrix depending upon the hydrophilic nature of matrix. By way of a further example a controlled~
releasing agent may be prepa~ed by a process compri~ing polymerizing a mixture of ab-O-Sil* EH5 (RTM) and 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, methyl methacrylate, divinyl benzene and t-butylperoctanate under a nitrogen atmosphere at 54~C ~or 12 hours and immersing the polymer matrix obtained into an NaCl aqueous solution containing methantheline bromide to im-pregnate methàntheline bromide in the interiox of matrix. Howeverr *Trade Mark -4-B

3~3 1 this process comprises two steps of polymerization and impregnationof the medicine, and therefore is a relatively expensive process to carry out.
As a result of study the following observations have been made:
tl) Since many physiologically active substances are imparted a physiological activity owing to their peculiar molecular structure, it is not desirable to contact them with other chemicals at com-paratively elevated temperatures. In this regard, it is considered to be advantageous to contain them to the extent possible in a high polymer carrier at lower temperatures;

(2) In order to adjust the structure of carrier so that the desired substance is contained in the carrier sufficiently uni-formly and released therefrom at an appropriate rate, it is ad-vantageous to mix the high polymer carrier in a monomeric state -~
with the desired substance before polymerization and then to polymerize the`mixture to contain the desired substance within the carrier; and

(3) It is necessary to impart to the polymer a pQrous internal ~0 structure or a structure having a broad surface area to facilitate ;~
the release of the desired substance at an appropriate rate, and it is advantagebus to design the structure and shape of the poly--; mer starting from the monomer.
~:. SU~ARY OF TEI~ INVENTION
- - --According to the present invention, a polymerizable monomer and a physiologically active substance are mixed or contacted in the following manner:
~- (1) A polymerizable monomer and a physiologically active substance . .

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1 and/or a non--polymerizable compound (i.e., crystallizable compound) which is insoluble or soluble in the monomer and freezes at low temperatures to be crystallized or is a crystal at room temperature are mixed to prepare a solution or suspension;
(2) A polymerizable monomer and a physiologically active substance are mixed, and the mixture is added to a medium insoluble in the polymerizable monomer with or wlthout adding an appropriate medium to prepare a microsphere comprising the polymerizable monomer and the physiologically active substance, which is then separated from the medium; and (3) A polymerizable monomer is casted to a ilm and a physio-logically active substance or a polymerizable monomer containing it and an insoluble medium are flo~ed on the surface thereof to prepare a monomer ~ilm having dispersed physiologically active substance on the surface.
Subsequently, the mixture of monomer and physiologically active substances prepared by any o~ these met~ods or the mixture containing a crystallizable medium is exposed to light or an ionizing radiation while cooling at low temperatures or ; 20 maintaining at room temperature without heating to polymerize the polymerizable monomer in the mixture to prepare a polymer . . .
composition containing the physiologically active substance in the interior or on the surface of polymer and having a function of releasing the active substance at a controlled rate.
In one modification of the present invention, one or more polymerizable monomers and a physiologically active substance are mixea in the presence or absence of a crystalliz-able substance, and added with an adsorbent, and, after making to an appropriate form, the mixture is irradiated with light or an ionizing radiation at a temperature below room temperature 5~

1 to polymerize the monomer to prepare a controlled releasing agent which contains the physiologically active substance and release it at an approriate rate. The modified process is characterized in that the controlled releasing property of physiologically active substance is controlled continuously over longer periods by, using an adsorbent in addition t~ polymerizable monomer, physiologically active substance and crystallizable substance.
In another modification, a physiologically active substance is dispersed or dissolved in a mixed solution obtained by dissolving a polymer or copolymer soluble in gastric or intestinal juice in a monomer polymerizable at low temperatures and mixing them uniformly, and after preparing to various forms of preparations, the resulting dispersion or solution is irradiated with light or an ionizing radiation at. a temperature below 0C to polymerize the monomer to prepare a polymer compos.iti.on which the elution rate of physiologically active . substance contained is controlled by pH.
: Further, in another modification, a mixture of one or more monomers polymerizable at a temperature below 0C containing phys io~o~ica/ly ~o a high molecular weight substance and 1-Y~ r nr~ active - substances is dropped or injecte~ into a medium at low tempera-` tures to prepare a form of spherical structure, and thereafter is irradiated with light or an ionizing radiation to polymerize :~ the monomers to prepare a polymer composition having a function of releasing the physiologically active substance at a controlled rate.
DETAILED nESC~IPTION OF PREFERRED-`EMBODTMENTS
Polymerizable monomers suitable for use in the present invention include all of various vinyl compounds, preferably 3~ ethylene dimethacrylate, diethylene glycol dimethacryla-te, 3~

diethylene glycol diacrylate, triethylene glycol dimethacrylate, triethylene glycol diacrylate, tetraethylene glycol dimeth-acrylate, tetraethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, diethylamino-ethyl methacrylater glycidyl methacrylate; epoxyacrylate, glycidyl acrylate, 2-hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate r hydroxybutyl methacrylate, hydroxybutyl acrylate r hydro~yhexyl methacrylate, hydroxyhexyl acrylate, butane diol dimethacrylate,;
butane diol diacrylate, propane diol dimethacrylate, propane diol diacrylate, pentane diol dimethacrylate, pentane diol d.iacrylate, hexane diol dimethacrylate, hexane diol diacrylate, :~ neopentyl glycol dimethacrylate, neopentyl glycol diacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trimethylolethane triacrylate, trimethylol-ethane trimethacrylate, polypropylene glycol diacrylate, poly-propylene glycol dimethacrylate, glycexol monomethacrylate, unsaturated polyester, etc. These compounds are monomers having a property of rapidly polymeriæing by light or an ionizing radiation at low temperatures, which is not crystallized at low temperature but easily forms a stable super cooling state or ` glass state, and which has a property prefe~ably as a medium or .
- carrier for supporting the desired physiologically active substance in an appropriate structure.
` However, in the present invention, in addition to the above described monomers, the following~-polymerizable monomers .~ which are capable of forming a polymer singly or in the coexist-ence o~ the abo-~e described monomer by irradiation can also be ~; empIoyed:
. 30 acrylic acid, methac~ylic acid, N-vinyl-2-pyrrolidoner acrylamide, methacrylamide, vinyl acetate, vinyl propionate ; -8-~2~

1 vinyl acetate, styrene, vinyl toluene, divinyl benzene, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, octyl methacrylate, lauryl methacrylate, benzyl methacrylate, cyclo- -hexyl methacrylate, stearyl methacrylate, methyl acrylate, butyl acrylate, ethyl acrylate-, maleic acid anhydride, etc.
Crystallizable ingredients contained in the polymer in the coexistence of polymerizable monomers in the present in-vention include water, dioxane, ethylene glycol, polyethylene gly-col, cyclohexane, benzene, acetic acid, propionic acid, butyricacid, urea, crotonic acid, maleic acid, malic acid, succinic acid, sorbic acid, itaconic acid, n-decane, n-menane, n-hexane, n-heptane, paraffin, stearic acid, palonitic ac.id, lauryl alcohol, ; octyl alcohol, caprilic acid, caproic acid, capric acid, stea.ryl alcohol, palmityl alcohol, butyl stearate, methyl stearate, methy~
acetate, ethyl acetate, butyl acetate, propyl acetate, priopinion~
amide, etc.
Physiologically active substances which can be used in the present invention include acetylchlorine, noradrenaline, serotonin, callicrein, gastrin, secretin, adrenalin, insulinr glucagon, ACTH, growth hormone, genadotropic hormone, oxytocin, vasopressin, thvroxin, testicular hormone(testosterorle~, ovarian hormone (estradiol), corpus luteum hormone, luteal hormone ;;
(progesterone), adrenacortical hormone, prostagladin, various ~ antihistaminic agents, antihypertensives, vasodilators, vaso-`~ protectors, stomachics and digestives, anti-diarrheals and intestinal absorbers, contraceptives, antiseptics and disinfect-ants for derma, agents for dermatozoonosis, antiphlogistic, acetylsalicylic acid, ibuprofen, phenacetin, mefenamic acid, maproxen, tiaramide, indomethacin, vitamins, various enzymes, .~ .

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an-titumor agents (bleomycin, sarkomycin, actinomycin D, cyclophosphamide, nitrogen mustard, triethylene thiophosphor-amide, mercaptopurine, methotrexate, 5-fluorouracil, mitomycin C, carzinophilin, chromomycin A3, 1-2(2-tetrahydro-furyl)-5-fluorouracil, radiopharmaceuticals, antibiotics (streptomycins, chloramphenicols, tetracyclines, erythromycins, trichomycins, bacitracins, colistins, polymixius, gramicidinsr penicillins, griseofulvins, etc.), sulfanilamide and its derivatives, an-tituberculosis drugs (TB preparations), antisyphilitics, antilepies, various biological preparations (vaccines, antiserums, to~ins and antitoxins, etc.), amebicides, anthelminics, ataractics, opthamological preparations (anticataract agents, antiglaucoma agents, etc.), various fish drugs, agricultural drugs, interferon, auxin, gibberelline, cytokinin, absinthic acidr other phytohormones, sex pheromone, aggregation pheromone, alarm pheromone, trail pheromone, cast pheromone, other pheromones, various natural insecticidal substances (pyrethroid, rotl;noid, nicotinoid, etc.), attractant, repellent, etc.
According to the present invention, tl) three compon-~0 ents of physiologically active substance, polymerizable monomer '- and crystallizable substance as described above are mixed to prepare a solution or suspension; (2) a mixture of physiologically active substance'and polymerizable monomer or the mi~ture added with'a high molecular ~eight substance soluble in the monomer is dropped into a medium insoluble in the monomer to prepare a microsphere;' or (3) a physiologically active substance or its solution or suspension is added onto the surface of polymeriz-able monomer film-casted to prepare a film of liquid mixture, and then the'solution or suspension, the microsphere or the film so obtained is irradiated with light or an ionizing radiation at room temperature or a lower temperature to polymerize the monomer ~3 .

1 to prepare a polymer composition containing the physiologically active substance in the interior or on the surface o~ the polymer and having a function of gradually releasing the active substance at a controlled rate.
In the present invention the light includes visible and ultraviolet rays from low and high pressure mercury arc lamps, light from photon factory, natural light condensed and controlled in intensity, and lights from xenone lamp, infrared lamp, etc. ~nd the ionizing radiation includes radiations from electron accelerator, isotope, etc., for example, ~-ray, ~-ray, electron beam, ~ ~ray, x-ray, etc. The temperature at the time of irradiating these lights or radiation is appropriately selected from the range of from room temperature, i.e. about 30C to -200C, preferably 0C to -100C, more preferably ~20~
to -80~. The reason is that even a physiologically active substance which is unstable for heat and or~anic chemicals and easily deprived of activity is comparatively stable in the domain of low temperature without bringing about any chemical change - and is easy to handle, and that at low temperatures a crystalliz-able component in the mixture is crystallized and polymerized to form porosities which increase the surface area for elution of physioloyically active substance and thereby the releasing rate of the desired substance can be easily controlled by adjusting the crystallizable component. And another advantage of low temperature is that most monomers used in the present invention become,at-a supercooling state at low temperatures, remarkably increased in viscosity and thereby the retention of physiologic-ally active substance becomes secure so that the active substance is effectively contained in the polymer without being scattered 30 and lost. Generally a method of using light or an ionizin~ ;

1 radiation is eEfective for the polymerization reaction in such low tempera-ture domain, but with other means it is difficult to carry out a polymerization effectively to contain the desired substance in ~he polymer. And, in general, when a polymer is directly added to the physiologically active substance and mixed therewith, it is necessary to heat the polymer at elevated temperatures to soften it, however, such heating at elevated temperatures is not proper since the physiologically active substance is in danger of being deteriorated and decomposed.
And also there is such a method as dissolving a polymer in a solvent and then, after dissolviny or dispersing a physiologically active substance in the resulting polymer sulution, removing the solvent by vaporization and the.like, however, it is complicated in operation t~ use and remove a large amount of solvent and it requires many hours and it is in danger of contaminating the surroundings~ and thus this method is.not preferable. Further-more, in order to maintain the desired substance in a carrier by the crosslinking structure of polymer and to control the releasing rate by changing the diffusion property in the carrier, it is o~ten necessary to use such a polymer as having a cross-linking structure and being easily dissolved in a solvent as a material for carrier. From such points the process of the present invention is considered to be advantageous, in which the desired substance is contained by the polymerization of monomers.
And then in case of mixing the desired substance and a polymer directly by kneading or mutual dissolution, such a method as growing the crystalli~able component to an appropriate size of crystal for adjusting the porous structure becomes impossible, ; and therefore, a technique of adjusting the structure of polymer so as to be suited to the release of the desired substance is remarkàbly:restricted.

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1 According to the present invention, in an embodiment, one or more po~ymerizable monomers and physiologically ac-tive substances are mixed in the presence or absence o~ a crystalliz-able substance and added with an adsorbent, and, after making to an appropriate form, the mixture is irradiated with light or an ionizing radiation to polymerize the monomer to prepare a polymer composiiion containing the physiologically active substance and having a ~unction of releasing it at a controlled rate. In this case, the adsorbent added includes gelatin, agar, collagen, active carbon, silica-gel, kaolin, ion exchange resins, synthetic fiber, foamed plastic, etc. And an adsorbent such as gelatin, agar, collagen, etc. is considered to control the elution o physiologically active substance by the swelling action thereo~
while active carbon, silica-gel, kaolin, ion exchange resins, etc. are considered to control the elution rate while partially adsorb~g the solution o~ physiologically active substance dissolved when the elution medium permeates into the composition.
By such actions, the controlled releasing property can be controlled over longer periods than in case the adsorbent is not existent by 5 to 10 times or more~ In the preparation of the polymer compositlon in this case, ~or 1 to 10 parts, by wei~ht, of polymerizable monomer, 1 to 10 parts, by weight, of physiologically a~tive substance, 1 to 5 parts, by wei~ht, o~
crystallizable substance and 1 to 30 parts, by weight, o~
adsorbent may be used. However, these composition ratios vary with the molecular weight of polymerizable monomer, but the ~; crystallizable substance is necessary to be completely dissolved in the polymerizable monomer.
In another embodiment~ a physiologically active substance is dispersed or dissolved in a mixed solution obtained ' .' ,,;: . , ' ' .

1 by dissolving a polymer or copolymer soluble in gastric or intestinal juice in a monomer polymerizable at low temperatures and mixing it uniformly, and, after preparing to various forms of preparations, the resulting dispersion or souution is irradiated with light or an ionizing radiation at a low tempera-ture below 0C to polymerize the monomer to prepare a polymer composition which the elution rate of physiologically active substance contained in controlled by pH. The elution rate of physiologically active substance in the preparations prepared using a polymer or copolymer soluble in acidic side according to the present invention is recognized to be remarkable in gastric juice (pH 1 to 4) but is restrained in intestinal juice (pH 5 to 8~, while, in case the polymer or copolymer component used is soluble in intestinal juice, the elution is restrained in gastric juice but is remarkable in intestinal juice. The polymer obtained by polymerizing the monomer component is a non-disintegration type of polymer which is not dissolved in gastric juice and intestinal juice. Therefore, when the polymer or copolymer component is eluted ~rom the preparations prepared 2~ accordin~ to the present invention to gastric juice or intestinal juice, a porous structure is ~ormed in the eluted place, and the physiologically active substance is released appropriately ~herefrom. The amount of polymer or copolymer component used in the- preparation o~ the polymer composition according to the present invention is preferably 5 to 60% based on the weight o~
monomer component. In case o~ above 60%, the polymer component is not dissolved in the monomer component, and in case of 40 to 60~, all of polymer components is not completely dissolved in -the monomer component. And in case of below 5%~ the object intended in the present invent,on cannot be attained. There~ore, 1 the most preferable amount of polymer component is 5 to 40% based on the weight of the monomer component. However, these compo-sition ratios vary with -the molecular weight of the polymer component. The physiologically active substance is used in an amount of 0.1 to 10 parts, by weight, per 10 parts, by weight, of clear uniform mixed solution of the polymer component and the monomer component.
In the preparations prepared accordin~ to this process, in case the physiologically active substance used is absorbed in stomach, the radical absorption and the inflammation of the stomach caused by the contact o~ a large amount of physiologic-ally active substance with the wall of the stomach can be suppressed and the absorbing rate can be controlled. And, in case of using a physiologically active substance which is mainly absorbed in an intestinal portion, the absorption in stomach is nonsense and becomes a cause of inflammation. Thus, the physio-logically active substance can be controlled by retarding the elution with pH of gastric juice as ]much as possible and ~ -increasing the dissolution and elution in an intestinal portion over a long period so that the number of times of administration can be decreased.
As the polymer component used in this process, "EUD~AGIT~ " is given as an example which is soluble in an aqueous solution of 1 to 4 in pH and "EUDRAGIT~ " and "EUD~AGIT~
(made by Rohm Pharma GMBH, West Germany) f and "MPM-05" and ~; "MPM-06" (made ~y ~anabe Pharmaceutical Co., Japan) are given as examples which are soluble in an aqueous solution of 5 to 8 in pH. ~owever, in additionf any other polymer or copolymer which the solubility varies with pH in an aqueous solution may be used. ;
Incidentally, "EUDRAGIT E" is a cation -type of polymer synthesized 5~

1 from dimethylaminoethyl methacrylate and any other neutral methacrylic acid ester. "EUDRAGIT L" and "EUDRAGIT S" are anion types of polymer synthesized from methacrylic acid and methacrylic acid ester. And "MPM-05" is methyl acrylate-methacrylic acid copolymer and "MPM-06" is methyl acrylate-methacrylic acid-methyl methacrylate copolymer. These polymer components must be completely soluble in the polymeriz-able monomer component.
Moreover, as the result of further research, it has been proved that physiologically active substances including medicines are scarcely decomposed by treating at a low tempera-ture below 0C and their effect as a medicine is not lowered at all, although these substances have hitherto been considered to be easily decomposed by the irradiation of radia-tion. The present -inventors have prepared on trial a polymer matrix having a controlled releasing property by polymerizing a polymerizable ; monomer which is vitrificable at low temperatures in the presence of physiologically active substance at a low temperature below 0C, and have found that the irradiation of radiation is the only means for polymerizing such ~itrificable monomer at `~ low temperatures helow 0C, that ~ray source ~60Co) is preferable as a radiation source though ~-ray, ~-ray~ electron beam, neutron beam, etc. may be used, and further that it is di~icult even at a lower temperature such as -78C to form a spherical polymer with the low temperature vitrificable monomer only.
Herein, the term "low temperature vitrificable monomer"(herein-after abbreviated to "vitrificable monomer") means a monomer which is not crystallized at a temperature below 0C but turns into a supercooling state and has the maximum initial polymer~
ization rate within the polymerization temperature domain below . . .
.

1 0~C near a temperature higher than the glass transition tempera-ture by 50C, and includes hydroxyethyl methacrylate, hydroxy-ethyl acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate~ hydroxybutyl methacrylate, hydroxybutyl acrylate~ glycol dimethacrylate, triethylene glycol dimethacrylate, polyethylene glycol #200 dimethacryla~e, polyethylene glycol ~400 dimethacryl-ate, polyethylene glycol ~600 dimethacrylate, diethylene glycol diacrylate, diethlene glycol dimethacrylate, triethylene glycol diacrylate, polyethylene glycol ~200 diacrylate, polyethylene glycol ~400 diacrylate, polyethylene glycol ~600 diacrylate, trimethylol propane trimethacrylate, trimeth~lol ethane trimeth-acrylate, trimethylol propane triacrylate, trimethylol ethane triacrylate, glycidyl methacrylate, etc. The vitrification effect comes out at 0C and remarkably at a temperature below -20C, but below -100C the polymerization velocity is remarkably lowered.
Since these vitrificable m~nomers are a supercooled liquid (highly viscous) at a temperature higher than the glass transition temperature (Tg), they turn back to the initial ~o supercooled liquid with the lapse of time even if they once change into a sphere. At a temperature below T~ the spherical monomer is almost impossible to be polymerized although it can maintain its spherical shape and thereby a spherical polymer cannot be prepared from the monomer. Then, the present inventors, as the result of further research, have found a fact that when a liquid prepared by coexisting an alkyl methacrylate polymer (hereinafter referred to as AMA polymer) crystallizable at a temperature below 0C in a vitrificable monomer and uniformly ; mixing them is added dropwise into a solvent cooled to a low ~ 30 temperature as -78C, a stable spherical particle o vitrificable .,~

1 monomer, the surface of which is coated with AMA polymer can be obtained, and, on the basis of the fact, have accomplished a process for preparing a polymer composition having a function of releasing a physiologically active substance at a controlled rate which comprises dropping or injecting a mixture o~ one or more vitrificable monomers containing 5 to 50~, by weight, of natural or s~nthetic high molecular weight substance and : physiologically active substance into a medium at low tempera-tures to form a spherical structure of 10 to 5,00~ lu in size and : 10 then irradiating it with light or an ionizing radiation at a temperauure below room temperature to polymerize the vitrificable monomer, and a process for preparing a polymer composition comprising a spherical matrix of 50 to 5,000 jU in size having a function of releasing a physiologically active substance at a : controlled rate which comprises dispersing 0.001 to 10 parts, by weight, of physiologically active substance to 10 parts, by weight, of vitrificable monomer containing 5.to 35~, by weight, of AMA polymer to uniformly disperse the active substance in the .: monomer, dropping or injecting the resulting dispersion into a medium cooled to -40 to -100C through a nozzle Of 0.1 to 4 mm and then irradiating it with ~-ray from 60Co or 127Cs, or ~-ray .
- from 90Sr or electron beam from accelerator to polymerize the vitrificable monomer and thereafter removing the solvent an~
- drying.
In the present invention, the spherical particles do not adhere. to each other after the polymerization since they are completely coated with ~ polymer. ~he dropping into a coolant may be carried out at atmospheric pressure or under pressure, and also may be accompanied by stirring. In addition to : 30 ~e dropping method, any method including injection method, which : is capable of making a droplet spherical, may be employed . -18-: . .

1 Natural or synthetic high molecular weight substances used in this process include polystyrene, Yinyl acetate resin, polymethyl methacrylate, polyvinyl pyrolidone, styrenemethyl methacrylate copolymer, methyl acrylatemethacrylic acid copolymer, 2-methyl-5-vinylpyridine-methyl acrylate-methacrylic acid copolymer, methyl acrylatemethacrylic acid-methyl methacrylate copolymer, polyvinylalcohol, acetic acid cellulose phthalate, cellulose acetate, dimethylaminoethyl methacrylate-methyl `
methacry~te copolymer styrenemaleic acid copolymer, hydroxy- ~
lC propyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl- -methyl cellulose, hydroxypropylmethyl cellulose phthalate, methyl cellulose,etc.
A coolant used in this process includes alcohols, alkyl celsol~es, p-dioxane, etc. and is not particularly limited if it is liquid at the time of making a sphere and polymerization, however, considexing a possibility that it may be remained in the polymer matri~, ethyl alcohol is par-ticularly preferable for animals, especially a human being.
The present invention is illustrated in greater detail in the following examples.
Examples 1 to 6 600 mg of potassium chloride, polymerizable monomer comprising 2-hydroxyethyl methacrylate (shown as "HEMA" in Table 1) and diethylene glycol dimethacrylate (shown as "DGD~" in Table 1) in any composition and polyethylene glycol #600 were mixed in a glass ampùle of 14 mm in inner diameter and cooled " to a dry ice-methanol temperature of -78C and therea~ter - irradiated with ~-ray from 60Co with a dose rate o~ 5 x 10 R/hr ;~
at the same temperature for 2 hours to obtain a composite in tablet. The elution of potassium chloride from the composite ~` .

1 obtained was conducted in distilled water of 6.1 pH at 100 r.p.m. agitation in the manner described in U~S.P. XIX. The elution property of potassium chloride, composition of polymeriz-able monomer and amount of polyethylene glycol #600 added were shown in Table 1.
Table 1 ~ . . .. ~ ... .~
Example Composition Amount of potassium chloride eluted (%) Composition of Amount of _ __ polymerizable polyethylene 3 hours 6 hours monomer (%) and glycol #600 after start after start 10 amount added added of test OI test _ __ ..... _ ........ ._ . . I
1 100 % HEMA, _ 45 65 2 0.5 ml _ 8 15 3 100 % DGDA, 0~35 ml 30 50

4 100 % HEM~; 0.10 ml 62 89 0.40 ml

5 70 ~ HEMA- 27 46 30 ~ DGDA, _

6 70 % HEMA- 0.25 ml 42 60 30 & DGDA;
0.25 ml _ _ _ Example 7 : ---. . .
3 g of bleomycin hydrochloride were uniformly dis-persed in a precopolymer sline obtained by previously irradiating a polymeriæable monomer comprising 95 parts, by weight, of di-ethylaminoethyl methacrylate and 0.5 parts, by weight, of trimethylolpropane trimethacrylate with ~-ray from 60Co with a dose rate of 1 x 106R/hr for 1 hour. The prepolymer was made into a film of 50 to 400 ~m in thickness using a casting apparatus made of glass plate and thereafter irradiated with ~-ray from 60Co with a dose rate of 5 x 105R/hr at -60C for 1 hour to -20- ;

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1 obtain a film containing bleomycin hydrochloride which has a wealth of flexibility.
Theelu-tion of bleomycin hydrochloride from the film obtained was conducted in distilled water of 6.1 in pH at 100 r.p.m. agitation in the manner described in U.S.P. XIX. The amount of bleomycin hydrochloride eluted was almost constant with time and after 168 hours 93% of the initial concentration were eluted.
Example 8 An aqueous solution of 5 mg of mitomycin C dissolved in 0.10 ml of distilled water and 0.40 ml of polyethylene glycol ~600 dimethacrylate containing 5% trimethylene glycol -dimethacrylate were mixed. This solution was dropped into a toluene coolant cooled to -78C through a nozzle to prepare a particle of about 2 mm in diameter, which was then irradiated with ~-ray from 60Co with a dose rate of 1 x 106~/hr at -78C
for 1 hour to obtain a spherical po]ymer matrix.
The elution of mitomycin C' from the matrices ob~ained was conducted in distilled water of 6.1 pH at 100 r.p.m. agitation in the manner described in U.S.P. XIX. The amount of mitomycin C eluted was 2% in 3 hours and 57% in 6 hours after start of test and reached 94~ in 12 hours.
Example 9 500 mg o~ betamethason and 0.8 ml of trimethylolpropane trimethacrylate were uniformly dispersed in an ampule of 8 mm in ; diameter and, after-cooled to -50C, were irradiated with ~-ray ~rom 60Co with a dose rate of 2 x 105R/hr for 3 hours to prepare a polymer matrix containing betamethason. The polymer matrix was crushed to below 50 ~m by means of a crusher and the elution of betamethason was conducted in distiIled water of 6.1 in pH

~ ~56~
g at 100 r.p.m. agitation in the manner described in U.S~P. XIX.
The amoUnt of betamethason eluted was constant with time and reached 92% in 48 hours after start of test.
Example 10 1,200 mg of contraceptive, norethandrolone, and 1 ml of trimethylolpropane trimethacrylate containing 30% tetra-methylolmethane tetraacrylate were uniformly dispersed in a glass ampule of 6 mm in inner diameter and, after cooled to -78~C, were irradiated with ~-ray from 60co with a dose rate of 5 x 105R/hr for 2 hours.
The elution rate of norethandrolone from the rod like polymer matrix was determined in purified water of 7.0 in pH at 50 r.p.m. agitation in the manner described in U.S.P. XIX.
- The amount of norethandrolone eluted was constant with time and reached 89% in 400 days after start of test.
Example 11 600 mg of ibuprofen and 3 ml of ethyleneglycol dimethacrylate were uni~ormly dispersed in a glass ampule of 8 mm in inner diameter and, after dearating (10 4 to 10 3 mmHg) several times, cooled to -78C and irradiated with ~-ray from 60Co with a dose xate o~ 5 x 10 R/hr for 3 hours to prepare a polymer matrix containing ibuprofen. ~he polymer matrix was crUshed to below 500 ~m by means of a crusher and the elution of ibuprofen was conducted in the second liquid (pH 7.5) described in J.P.IX at 100 r.p.m. agitation in the same manner as described in UOS~PO XIX. The amount of ibuprofen eluted was constant with time and reached 81~ in 12 hours after start of test.
Example 12 5 parts, by weight, of bleomycin hydrochloride were 0 added to 10 parts, by weight, of dieth~lene glycol dimethacrylate .

, .

`5~
1 containin~ 15%, ~y weigllt, of pol~meth~l methacrylate, and the resulting monomer solution containing bleomycin hydrochloride was added dropwise through a nozzle of 0.5 mm in inner diameter into ethanol cooled to -78C by dry ice-ethanol in such a state that the bleomycin hydrochloride was uniformly dispersed in the monomer liquid by stirring. Thereafter ~-ray from 60Co was irradiated thereto with a dose rate of 2 x 105R/hr at -78C for 3 hours. After irradiation, it was removed ethanol and dried to obtain a hard spherical polymer matrix of 1 mm in average diameter. Unreacted monomer was not detected by gas chromatography~
When the spherical matrix was placed into 1,000 ml of distilled water at 37C and stirred at 100 r!p.m. to elute out bleomycin hydrochloride, the elution rate was observed to be const~nt during one month. The total amount of bleomycin eluted reached 90% of the initial charge.

3 parts, by weight, of cyclophosphamide were added to ` 10 parts, by weight, o~ 2-hydroxyethyl methacrylate containing 10~, by weight, o~ polymethyl methacrylate, and the resulting ~` 2~ dispersion was dropped into ethanol cooled to -78~C through a nozzle of 2 mm in inner diameter in such a state that the cyclophosphamide was uni~ormly dispersed in the monomer liquid by stirring to prepare a spherical monomer. Thereafter, the ethanol mixture containing the spherical monomer particles was ;~ irradiated with ~-ray from 60co with a dose rate of 8 x 105R/hr at -78C for l hour. After irradiation, ethanol, was removed and dried to obtain a somewhat hard spherical polymer matrix of 3.5 mm in average diameter. Unreacted monomer was not detected by gas chromatograpny. The spherical polymer matrix containing ~; 30 cyclophosphamide was charged into 1,000 ml of distilled water 1 at 37C rOtating at 100 r.p.m. The elution rate of cyclo-phosphamide from the matrix was constant during 12 hours. The total amount of cyclophosphamide eluted for 12 hours corresponded to 85% of the initial charge.
Example 14 4 parts, by weight, of 1-2(2-tetrahydro-furyl)-5-fluorouracil were added to 10 parts, by weight, of trimethylol-propane trimethacrylate containing 15%, by weight, of polymethyl methacrylate and the resulting monomer dispersion was injected into ethanol cooled to -78C through a nozzle of 0.15 mm in inner diameter under pressure while stirring. Thereafter, the spherical monomer in the ethanol coolant was irradiated with ~-ray from 60co with a dose rate of 1 x 10 R/hr at -78C for 6 hours. After irradiation, ethanol was removed and dried to obtain a hard spherical polymer matrix of 0.3 mm in average diameter. Unreacted monomer was not detected by gas chromato-graphy.
The spherical polymer matrix containinc~ 1-2(2-tetra-hydro-uryl)-S-fluorouracil was charged into 1,000 ml of distilled water at 37C rotating at 100 r.p.m. The elution rate of 1-2(2-tetrahydro-furyl)-5-fluorouracil from the matrix was ` constant during 2 months. The total amount eluted for 2 mon-ths reached 88~ of the initiàl charge.
Example 15 ; 1 part, by weight, of betamethason was added to 10 parts, by weight, of glycidyl methacrylate containing 10~ by weight, of polystyrene and betamethason was uniformly dispersed in the monomer by stirring. And then the monomer containing betamethason was injected into a medium cooled to -78C by dry 3~ ice and ethanol under pressure of nitrogen gas. Thereaf-ter, :~, - .

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L~5~

1 the monomer in the medium was irracliated with ~-ray from 60Co with a dose rate of 1 ~ 10 R/hr at -78C for 1 hour. A~ter irradiation, ethanol was removecl and dried to obtain a hard spherical polymer matrix of 0.030 mm in average diameter. Unreacted monomer was not de-tected by gas chromatography. The spherical ~,~
polymer matrix containing betamethason was charged into 1,000 ml o~ distilled water at 37C rotating at 100 r.p.m. The elution rate of betamethason from the matrix was constant during 3 days, and the total amount eluted reached 91% o the initial charge.
Example 16 10 parts, by weight, of polyethylene glycol ~600 were added to 10 parts, by weight, of diethylene ylycol dimeth--acrylate containing 10~, by weight, of polyvinylalcohol, and ~urther 1 part, by weight, of indomethacin was added thereto and uniformly dispersed in the monomer solutlon. The monomer solution containing indomethacin was dropped into an ethanol medium cooled to -78C in the same manner as described in Example 1~.
Thereafter, it was irradiated with ~-ray from 60Co with a dose rate of 7 xlO5R/hr at -78C ~or 1 hour. After irradiation, etaanol was removed and dried to obtain a spherical polymer matrix of 2 mm in average diameter. Unreacted monomer was not detected by gas chromatography. The spherical matrix containinq indomethacin was charged into 1,000 ml of distilled water at 37~C rotating at 100 r.p.m. to check the elution property. The elution rate of indomethacin from the matrix was constant during 7 hours a~d the total amount eluted reached 85~ of the initial charge.
Example 17 303 parts, by weight, of bleomycin hydroxhloride were added to 10 parts, by weight, of trimethylolpropane triacrylate -25- ~

1 containing 10%, by weight, of vinyl acetate polymer, and the resultiny monomer solution con-taining bleomycin hydrochloride was dropped into ethanol cooled to -78C by dry ice-ethanol through a nozzle of 0.4 mm in inner diameter in such a state that the bleomycin hydrochloride is uniformly dispersed in the monomer liquid Thereafter, a light (maximum energy wave length 3,600 A) from a high pressure mercury vapour lamp made by Toshiba Co. was irradiated there-to for 2 hours. After irradiation, ethanol was removed and dried to obtain a hard spherical matrix 10 of O. 9 mm in average diameter. Unreacted monomer was not detected by gas chromatography. When the spherical matrix was charged into 1,000 ml of distilled water at 37C and stirred at 100 r.p.m. to elute out bleomycin hydrochloride from the matrix, the elution rate was observed to be constant during 25 days. The total amount eluted reached 85~ of the initial charge.
Exam ~
Example 17 was repeated except irradiating ~-ray from 90Sr with the total dose of 7 x 10 R/hr at -78C in place of using the high pressure mercury vapour lamp. The elution of bleomycin 2~ hydrochloride from the spherical matrix (0.9 mm) obtained was almost the same as in Example 17.
In the following examples 19 to 24, the elution test o~ chemicals from the preparations obtained according to the present invention was conducted at 37 ~ 0.5C in the manner described in U.S.P. XIX while rotating a stainless steel basket at 100 r.p.m.
Example 19 - 10 parts, by weight, of aspirin were added to 10 parts, by weight, of clear uniform mixed solution of 2-hydroxyethyl 3~ methacrylate containing 30~, by weight, of "EUDRAGIT~ " in a .

-1 glass ampule which was then degassed and sealed, and then wasquenched to -78C (in a dry ice-methanol coolant) in a state that aspirin is apparently uniformly dispersed ln the clear uniform mixed solution, and thereafter was irradiated with ~-ray from Co with a dose rate of 5 x 105R/hr at -78C for 2 hours to polymeriæe 2-hydroxyethyl methacrylate completely to prepare a preparation. The preparation so obtained was crushed to 12 to 32 meshes ~d then provided to the elution test. The amount of aspirin eluted in an aqueous solution of 3.0 in p~ reached 96%
1~ f the intiial charge in 2 hours and the elution rate was observed to be constant.
The amount of aspirin eluted in an aqueous solution o~

7.0 in p~l reached 35~ of the initial charge. For comparison the amount of aspirin eluted from a preparation prepared under the same condition except not coexisting "EUDRAGIT E" corresponded to 19% and 22% of the initial charge in an aqueous solution of 3.0 and 7.0, respectively, in pH.
Example 20 -~ B parts, by weight, of potassium chloride were dispersed 2~ and mixed to 10 parts, by weight, of polymerizable monomer mixed solution comprising 70% of 2-hydroxyethyl methacrylate and 30~
of trimethylolpropane trimethacrylate containing 25~, by weight, of "EUDRAGIT~", and thereafter the dispersed mixed solution was poured into a vinyl chloride polymer tube of 4 mm in inner diameter and simultaneously quenched to -78C (in dry ice-methanol coolant), and, in this state, was irradiated with a dose rate of 1 x 105R/hr under a nitrogen atmosphere to copolymerize 2-hydroxyethyl methacrylate and trimethylolpropane trimeth-acrylate to convert them to a polymer by 100~. The resulting high polymer composition was cut to a chip of 4mm in diameter 1 and 4 mm in height by a cutter. When the elution test of potassium chloride from the chip was conducted in an aqueous solution of 3.0 in pH, the amount eluted for 5 hours reached 31%
of the initial charge. In an aqueous solution of 7.0 in pH the amount of potassium chloride eluted reached 94% of the initial charge for 6 hours. For comparison, the amount of potassi~
chloride eluted from a high polymer composition prepared under the same condition except not coexisting "EUDRAGIT L" correspond to 16% of the initial charge in an aqueous solu~ion o~ 3.0 in pH
and to 27% in an aqueous solution of 7.0 in pH.
Example 21 6 parts, by weight, of creosote were added and mixed to 10 parts, by weight, of hexanediol monomethacrylate containing ; 15%, by weight, of "~PM-06" and the resulting mixed solution was injected into such a glass casting apparatus as making a ~ilm of 50 ~ in thickness, and, thereafte~, was irradiated with electron beam from an electron beam accelerator o~ 2MeV with 1 x 106 rad under a nitrogen atmosphere at -60 ~ 5C to polymeri~e hexanediol monomethacrylate. The amount of creosote eluted from the resulting film was 9% of the initial charge for 4 hours in case of an aqueous solution of pH 3 0 and 55% in case of an aqueous solution of pH 7Ø
; Example 22 4 parts, by weight, of bleomycin hydrochloride, 10 parts, by weight, of a mixture consisting of 30% of glycidyl methacrylate and 70% of trimethylolpropane trimethacrylate and 4 parts, by weight, of silica-gel in below 200 meshes were dispersed and mixed, and the resulting dispersion mixture was placed into a casting apparatus made of glass plate and irradiated with ~-ray from 60co with a dose rate of 1 x 105R/hr at an irradiation -2~-1 temperature of _70 t 5C for S hours to prepare a film of 100 ~u in thickness.
The amount of bleomycin hydrochloride eluted from the film preparations obtained was almost constant wi-th time and was observed 92% of the initial charye to be eluted during 150 days.
Eor comparison, in case of film preparations prepared under the same condition except not coexisting silica-gel, the amount of bleomycin hydrochloride eluted was 90~ of the initial charge during 25 days.
Example 23 1 0 ~
3 parts, by weight, of 5-fluorouracil, 5 parts, by weight, of hydroxyethyl acrylate, 2 parts, by weightr of polyethylene glycol ~400 and 3 parts, by weight, of active carbon in 65 to 115 meshes were dispersed and mixed, and the resulting dispersion mixture was poured into a polyethylene tube of 5 mm in inner diameter and simultaneously was quenched to -78QC (dry ice-methanol). Thereafter, the mixture was irradiated with ~-ray from 60Co with a dose rate of 5 x 105R/hr in a nitrogen atmosphere for 2 hours to convert hydroxyethyl acrylate-to a polyrner by 100%.
The preparation so prepared was cut to a pellet of 5 mm in diameter and 5 mm in height. When the amount of 5-fluorouracil eluted from the preparation was determined, the elution rate was observed to be constant during 35 hours and the amount reached 95% of the initial charge. For comparison, the amount of 5-fluorouacil eluted from a preparation prepared under the same condition except not coe~isting active carbon was 89% for 6 hours.
Example 24 3 parts~ by weight, of progesterone, 6 parts, by weight, ' .

.
, 1 of a mix-ture consisting of 20% of diethylene glycol dimethacrylate and 80% of trimethylolpropane trimethacrylate, 2 parts r b~
weight, of polymethyl methacrylate and 3 parts, b~ weight, of Amberl~st 15 (made by Organo Co.) were dispersed and mixed, bu.t, polymethyl methacrylate was pxeviously dissolved in a mixed solution of ethylene glycol dimethacrylate and trimethylol-propane trimethacrylate. The resulting dispersion mixture was dropped into an ethanol coolant cooled to -78C to prepare a monomer capsule o~ 4 mm in avera~e diameter and thereafter 10 irradiated with ~-ray from 137Cs with a dose rate of 1 x 105R/hr at this coolant temperature for 8 hours to prepare a polymer capsule containing progesterone. The elution rate of proge~sterone from the polymer capsule was constant over 13 months and the total amount reached 87~ of the initial charge. For comparison, the amount of proyesterone eluted from a polymer capsule prepared under the same condition except not coexisting Amberlyst 15 reached 84% ~or 2 months.
Example ? 5 A dispersion mixture comprisin~ 3 parts, by weight, of methyl salicylate, 3 parts, by weight, of gelatin and 6 parts, . , .
by wei~ht, of 2-hydroxyeth~l methacrylate was poured into a flat :
;~ ~ype of glass ampule and thereafter irradiated with electron beam from an electron beam accelerator of 2MeV with 1.5 x 106 :. rad under a nitrogen atmosphere at -70 + 5c. The preparation obtained was crushed to 32 to 65 meshes. The elution rate of methyl salicylate from the crushed preparation was constant over 48 hours, and the total amount reached 96~ of the initial charge. For comparison, the amount of methyl salicylate eluted from a preparation prepared under the same condition except not ; 30 coexisting gelatin reached 90~ for 3 hours.
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1 In the process of the present invention, starting from a mixture of monomer and physiologically active substance, the composition is prepared by polymerizing it. The function of releasing the physiologically active substance from the composition can be changed and controlled to the desired releasing rate by selecting the kinds of monomer or devising a combination and composition in plural monomers system, considering the affinity of monomer and its polymer for physiologically active substance, crystallizable component and medium in an environment in which the composition is used, and others, according to the molecular size, chemical properties, solubility, etc. of the physiologically active substance, or by devising the kind and amount of crystallizable component added at need, the temperature and cooling velocity when the component is crystallized, the tempera-ture and dose when the polymerization is effected by irradiation and other polymerization conditions.
In addition to microsphere, film, etc., the mixture of monomer and physiologically active substance can be casted into various shapes of frame or mold to form a block, fiber, tube and ~ 20 other shapes which are then polymerized to provide various shapes -~ of controlled releasing composition. The polymer composition so ; obtained can be not only utilized in medical uses such as thera-pentics,prophylactic diagnosis and inspection in a form of - internal medicine, suppository, external remedy, artifioial internal organs, or the like, but also can be 1~roadly utilized in the ~ields of agriculture, gardening forestry, f~shery, animal ~; husbandry, etc. in a form of fish drug, agric~ltural chemicals, insecticide.s, anthelmint, or the like. Furthermore, the mixture can be utilized for rearing and culture of vegetation and - 30 microorganisms using a composition containing growth hormone, , N ~ 3~

1 multiplication aecelerator of microorganisms, inhibitor for interrupting substance, etc., and also can be utilized for control and acceleration of reaction in food industry and medical industry using a composition containing stabilization ion for enzyme, assistant for enzyme reaction, inhibitor for interrupting substance, etc.

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Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a polymer composition contain-ing a physiologically active substance characterized by contacting one or more polymerizable monomers and said physiologically active substance to make it into a specific shape and irradiating it with light or an ionizing radiation at a low temperature below room temperature to polymerize said polymerizable monomers.

2. The process as set forth in claim 1 wherein the contact of polymerizable monomer and physiologically active substance is carried out by mixing them in the presence of crystallizable substance.

3. The process as set forth in claim 1 wherein said shape is selected from the group consisting of fibers, wires, strings, discs, rods, cylinders, needles, nails, pellets, spheres, micro spheres, powders, films, sheets or plates.

4. The process as set forth in claim 1 wherein the contact is carried out by mixing the polymerizable monomer and physiologically active substance in the presence of crystallizable substance and thereafter an adsorbent is added to the mixture prior to irradiating the mixture,

5. The process as set forth in claim 4 wherein said adsorbent is selected from gelatin, agar, collagen, active carbon, silica-gel, kaolin, and an ion-exchange resin,

6. The process as set forth in claim 1 wherein the contact is carried out by dispersing or uniformly mixing said physiologically active substance in a mixed solution comprising a polymer or copolymer soluble in a pH within the range of 1 to 10.0 and a monomer polymerizable at low temperatures and the irradiation temperature is below 0°C.

7. The process as; set forth in claim 6 wherein the amount of said polymer or copolymer completely dissolved in a solution of 1 to 10.0 in pH is 5 to 60% based on the weight of said monomer.

8. The process as set forth in claim 6 wherein the amount of physiologically active substance is 0.1 to 10 parts, by weight, per 10 parts, by weight of said mixed solution,

9. A process for preparing a polymer composition having a function of releasing a physiologically active substance at a controlled rate which comprises dropping of injecting a mixture of one or more monomers vitrifiable at low temperatures containing 5 to 50%, by weight, of natural or synthetic high molecular weight substance and said physiologically active sub-stance into a medium non-crystallizable at low temperatures in which said mixture is insoluble or has low solubility to make it into a shape of spherical structure, and thereafter irradiating it with light or an ionizing radiation at a low temperature below room temperature to polymerize said monomers.

10. The process as set forth in any of claim 1, 2 or 9 wherein said ionizing radiation is ?-ray from 60Co or 137Cs, .beta.-ray from 90Sr or electron beam from an accelerator.
11. A process for preparing a polymer composition comprising a spherical matrix of 50 to 5,000 µ in size having a junction of releasing a physiologically active substance at a controlled rate which comprises adding 0.001 to 10 parts, by weight, of said physiologically active substance to 10 parts, by weight, of monomer vitrifiable at low temperatures containing 5 to 35%, by weight, of polyalkyl methacrylate to uniformly disperse said active substance in said monomer, dropping or injecting the resulting dispersion into a medium cooled to

Claim 11 continued ...

-40 to 100°C through a nozzle of 0.1 to 4mm, and thereafter irradiating it with ?-ray from 60Co or 137Cs, or .beta.-ray from 90Sr, or electron beam from accelerator, to polymerize said mono mer.

12. A process as set forth in claim 9 wherein said natural or synthetic high molecular weight substance is selected from the group consisting of polyalkyl methacrylate or polystyrene.