TW382598B - Physiologically active substance-prolonged releasing-type pharmaceutical composition - Google Patents

Abstract

A prolonged releasing pharmaceutical preparation is provided carrying a physiologically active sub-stance, particularly, calcitonin gene-related peptide (CGRP) or a maxadilan (MAX). This pharmaceutical preparation can attain the expected effects by incorporating the physiologically active substance into a combination, as carriers for the physiologically active substance, of a cellulosic polymer and at least one auxiliary component selected from the group consisting of fats and oils, waxes, fatty acids, saccharides and polyacrylate ester derivatives. The pharmaceutical preparation can conveniently be used, in living bodies, particularly as an intrathecal implantation-type preparation.

Description

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_ V. Description of the Invention (f) Background of the Invention Field of the Invention The present invention relates to a pharmaceutical preparation that can release physiologically active substances in a controlled state. The medicinal preparations are specifically targeted at physiologically active peptides, such as statin gene-related radon (CGRP) and mandibular hormone (MAX 8). »The medicinal preparation of the present invention can be used as an in vivo implantable type, especially an intrathecal implantable physiologically active substance Winding-type system. BACKGROUND OF THE INVENTION A sustained-release (hereinafter, the same meaning as gradual or delayed release) type preparation, in which when a drug or a physiologically active substance is administered to a living body, the dissolution release of the drug in the living body is controlled so that its absorption can be adjusted. The research time has been quite long. For example, there are known a method of coating a drug with various coatings, a method of mixing a drug with rhenium or a macromolecular matrix, and the like. However, when the following diseases are treated, physiologically active substances are administered intravenously, and these physiologically active substances cannot enter the brain due to the blood-brain barrier. As for the method of directly injecting physiologically active substances into the brain, one method is to insert a catheter during surgery to slowly supply the drug to the brain, but because the device is expensive and the risk of infection is high, it is difficult to call this method miscellaneous. Methods. For example, delayed cerebral vasospasm occurs after subarachnoid hemorrhage, and the onset of morbidity is delayed. In addition, it is maintained for a long period of time. Therefore, the box requires a method of inserting a catheter for administration and a method of continuous administration into a vein. However, the current state of the industry is that no method has yet been developed to obtain exact results. When attention is turned to physiologically active peptides, betinostatin gene-related peptides (CGRP) and mandibular hormones (MAXs), the diseases that have not been proposed are particularly targeted for this paper. The Chinese National Standard (CNS) 8-4 specification (210X297) Li) (Please read the notes on the back before filling in this page)

A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (>) entanglement-type pharmaceutical preparations with active substances that are effective. The inventors hope to develop peony containing these active substances and can be effectively used for various diseases. System When referring specifically to CGRP and mandibular hormones, such as EALerne !, etc., International Publication No. WO 91/00293 shows that these substances are extremely susceptible to mammalian induced vasodilation and temporary immunosuppressive effects. Proteins of interest; however, after Lerner et al. Report, no suggestion has been made of a wrap-around medical preparation of these ingredients. In this regard, " mandibular hormone " was described in the previous bulletin as a protein derived from the salivary lysate of the sand fly Lutzomyia longipalpis, and was therefore named " mandibular hormone " (for example, J. Biol. Chem. , vol. 2 67, 1 0 6 2-1 0 6 6, 1 9 9 2). In the aforementioned reference, Lerner et al. Stated that by expressing recombinant mandibular hormone, W 0 9 1/0 0 2 3 3 showed that the mandibular analogue also has vasodilating activity. Other inferior mandibular analogues with vasodilator activity are shown in Onuma, E.A. Lerner et al., Life Chemistry 1 9 3: Okada, 145-148. Interesting report on the pharmacological effects of CGRP, Shimizu et al., Neurosurgery 22 (2): 131-139, 1994 shows that when using the rabbit subarachnoid hemorrhage model, some CGRP (human a CGRP: B acheb Feincheaikalien, AG, Budendorf, Switzerland) Sterile solution was injected into the animal's cerebellum snooze pool to obtain the vasoconstrictor effect. However, this method is often unsatisfactory for the prevention or treatment of the aforementioned morbid or delayed manifestations of cerebral vasospasm. In addition, because this injection is extremely dangerous, it is necessary to monitor the physiological substance aqueous solution during the injection process. Injected into the cerebellum bulbar cistern. This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please read the notes on the back before filling out this page)-Ordered by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed A7 B7 V. Invention Description ( 4) Therefore, the object of the present invention is to provide a medicinal preparation which can effectively prevent or treat cerebral vasospasm and its preparation method. Summary of the Invention The inventor hopes to accomplish the foregoing objective, and has such physiologically active substances and various carriers. The combination was thoroughly researched, and it was unexpectedly discovered that when using a lutein-based polymer as a main carrier, a physiologically active substance, a particular physiologically active peptide has a controlled release property. Further research results also found that MAXs themselves can effectively prevent and treat cerebral vasospasm, regardless of their dosage form. Another important discovery of the inventors is a method for implanting a wrap-around pharmaceutical puppet containing a compound having a vasodilating effect into the brain. This method has not been tried so far as a method for preventing or treating cerebral vasospasm. Methods, which have not been shown or suggested in scientific literature, can be extremely effective in preventing or treating diseases. Thus, the present invention is directed to a peony preparation containing an effective amount of a physiologically active substance and capable of holding a physiologically active substance, wherein the carrier of the physiologically active substance comprises a savirin polymer and at least one selected from the group consisting of fats and A combination of auxiliary ingredients of oils, tinctures, fatty acids, sugars and polyacrylate derivatives. As for more specific specific examples, the present invention is directed to a pharmaceutical preparation containing an effective amount of a physiologically active substance and capable of sustaining the physiologically active substance, wherein the physiologically active substance is one or more compounds selected from CGRP and MAXs, and This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

n · — inmnm-I nn-I-II In I-n--I nn II nn I A7 £ 7 ________ V. Description of the invention (4) The carrier of the physiologically active substance includes 10 to 90 wtz cellulose ether derivatives, 1 to 30wtX fat or oil or tincture, and 1 to 30wtJK fatty acids, based on the total weight of the peony composition; or a carrier of physiologically active substances including 10 to 90wtJ! Cellulose derivatives, 1 to 40 , Based on the total weight of the drug composition; or the physiologically active substance carrier is a combination of the following: to 90 »1; 31 crystalline cellulose and 0.01 to 10 wtX polyacrylate derivatives, and at least one Or more ingredients selected from 1 to 30wU fatty acids, 1 to 3GwtX fats or oils, and 1 to 3 () Wt! K wax, based on the total weight of the pharmaceutical preparation; or a physiologically active substance carrier including about 50% by weight hyaluronic acid and about 5flwtX cationic polyacrylic acid derivative, based on the total weight of K Pharmaceutical M. As for another skeletal example, the present invention is directed to a method for preventing or treating cerebral vasospasm, including administering an effective amount of at least one MAXs to a living body (please read the precautions on the back Φ before filling this page). Body 1 Another anti-release needle is used to prevent pre-wrapping. The material and material properties are consistent with the material properties of the hair. The rationale will be included as a wrapper, and the legalized party will use it as a spasm. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ Tube or blood therapy 帛 blood or blood treatment S treatment or type £ 1 1 1 tube sauce extension 2 pre-equipped 0 system 剤 in-process medicine needle image 轚 your type The combination of hair release and chemical conversion of this type 0 * * into the case of the way to implant the body with the sheath of the brain to sharpen one thing into the B combined hitting the plant and reducing spasm in the tube system to use blood medicine As a brain _ Zhang therapy expansion treatment Figure 1 shows the release of CGRP from the pharmaceutical preparations PI, P-II and P-III (prepared in Examples 1, 2 and 3 respectively) of the present invention in a test tube test. National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (situation diagram; Figure 2 shows the mandibular hormone (sequence miscellaneous number: 3) produced in the test tube test by P-VII, P-VIII and P-IX (prepared in Examples 7, 8 and 9) Release diagram; Figure 3 shows the release of CGRP from the pharmaceutical preparation P-XI (prepared in Example 11) of the present invention; Figure 4 shows the release of CGRP from the peony preparations P-XIII and P- of the present invention in a test tube test XIV (prepared in Examples 13 and 14) release diagrams; Figures 5 and 6 to 8 show CGRP in the pilot test from the pharmaceutical preparations P-XV-1 and P-XV-2 of the present invention ( Both were prepared in Example 15), and release maps of P-XVI to P-XX (prepared in Examples 16 to 20); Figure 9 shows that CGRP is made thin by the hair-emitting drug of the present invention implanted in the brain of rabbits Figures of release of lp-II; Figures 10 and 11 show the _ subarachnoid area of the animal model, which is particularly specific to the subarachnoid space. The preparations PV and P-VI of the present invention are implanted and the vasodilation is observed. Results; Figure 12 is a graph showing the change in the concentration of CGRP in CSF and the stability of CGRP in CSF when an aqueous solution of CGRP is administered to the stomach by the cerebellar puncture method; Figure 13 printed by the Consumer Cooperative shows the results of vasodilation test administered to the CGRP aqueous solution by the cerebrovascular puncture method. Figure 14 shows the use of the preparation P-VIII (containing N-terminally modified mandibular hormone, sequence identification number: 3) The vasodilation test results similar to Figures 10 and 11; Figure 15 shows the preparation of the present invention P-I1 by changing the CGRP concentration of CSF. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Economy Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards of the People's Republic of China 5. The results of the in-tube release test of the invention description (b); and Figure 16 shows the modified mandibular hormone (sequence identification number: 3) The effect of inhibiting vasospasm when cerebrovascular spasm method is administered to animals with cerebral vasospasm mode. Mushroom Bfl: > Detailed description The cellulose polymer used in the present invention contains, for example, cellulose ether derivatives such as hydroxypropyl lavagen, methylvinyl vitamin, hydroxypropyl methylvinyl, hydroxyethyl hydrazone Among the vitamins and carboxymethyl ferritin; and the crystalline androsterin and vitamine ether derivatives are preferably hydroxypropyl oryzanol. The amount of this polymer in pharmaceutical preparations varies with the type of adjuvant combined and the type of physiologically active substance carried on it, and is determined by considering the release start time and release hold time, so the mix amount is not limited , But it is usually based on the total weight of the pharmaceutical preparation of 10 to 90 wtX, preferably 40 to 60 wtX. Fats and oils or tinctures include hardened oils, cocoa butter, tallow, lard, beeswax, brazilian brown brain, white brain, etc. Preferred are hardened oils. Its mixing amount is also not limited, and it can be determined by considering the release start time and release performance time, but it is usually based on the total weight of the pharmaceutical system 1 to 30 wU, preferably 10 to 20wt3! E Unless otherwise defined in the S line later Wtx notation is based on the total weight of the pharmaceutical preparation. Fatty acids include saturated or unsaturated carboxylic acids containing 12 to 22 p-atom such as stearic acid, lauric acid, myristic acid, isostearic acid, palmitic acid and sorbic acid. Stearic acid is preferred. Its mixing amount is not limited, and it is also determined by considering the release start time and release entanglement time, but it is usually 1 to 30 w 13 !, preferably 10 to 20 wt X β 8-This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

* tT Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (7) Gambling products include sucrose, lactose, glucose, fructose, maltose, dextrin, trehalose, kubusan, etc. Preferred are lactose and glucose. The disintegrability of the xu release preparation can be adjusted by adding sugar. That is, the disintegration speed can be accelerated by adding 量 to the mixing amount. The mixing amount is not limited, and the release start time and release setting time are also considered, but it is usually 1 to 40 wts !, preferably 10 to 30 wU. When the amidines are used as adjuvants, particularly in combination with the aforementioned cellulose ether derivatives, the desired effect can be obtained without the need to blend fats or oils or brain or fatty acids which are auxiliary ingredients.

When crystalline streptavidin is used as a cellulose polymer, it is recommended to use it with polyacrylate derivatives such as poly (methacrylic acid-copolymerization-ethyl acrylate), poly (methacrylic acid-copolymerization-methacrylic acid) Ester) and poly (methyl methacrylate-copolymerization-ethyl acrylate), preferably Eudrag L30D-5.5 and L100 (trade names, obtained from the polyacrylic acid ester derivative of Lane Company, Germany) The compounding amount is usually 0.01 to, preferably 0.1 to 5 vtU. Among the physiologically active substances mentioned later, suitable carriers for use in combination with CGRD or MAX s are also worth mentioning, including ionic complexes of hyaluronic acid and cationic polyacrylic acid derivatives. As for hyaluronic acid, another one can be derived from a wide range of natural sources, such as mammalian connective tissue, cockscomb, coccus capsular, etc. (from / S-N-fluorenyl-D-glucose-amine and -D- »Any of linear polymers derived from glucuronic acid derived through alternating bonds) Any of the appropriate cationic polyacrylic acid derivatives such as poly (methyl methacrylate-copolymerization-methyl methacrylate) Acid butyl-copolymer-dimethylaminoethyl Methacrylic acid ester) and poly (ethyl acrylate-copolymerization-methacrylic acid. Sulfonic acid methyl-9-This paper size applies to China National Standard (CNS) A4 Regulation (210X297 mm) ------- -© ^ 1 ------ tr ------- 0 (Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Masonry Consumer Cooperative A7 £ 7 ___ 5. Description of the invention (I?) Ester-copolymerization-trimethylammonium ethylmethacrylic acid vinegar hydrochloride) contains, for example, excellent agent E and excellent agent ES (trade name available from the German company Lame, so that its mixing ratio is suitable for using almost equal amounts) A variety of physiologically active substances can be used without particular restrictions on the type and type of action, as long as the peony drug system of the present invention can be made and significant effects can be achieved through entanglement release. These physiologically active substances include, for example, epinephrine , Abscisic acid, arginine tube oxytocin, proangiogenin, vasopressin, angiotensin I converting enzyme, gastric juice inhibiting peptides, insulin, insulin-like growth hormone, S factor, erythropoietin, Prolactin, prolactin-releasing hormone, lutein, oxytocin , 2-octyl-7-bromoacetamidinate, endocrins, gastrin, gastrin secretion accelerating peptide, gastron, cleansing vitamin D3, bradykinin, calcitonin, inhibitor Calcitonin Gene Makeup (CGRP), kininogen, thymus hormone, glucagon, glucocorticosteroids, vasoactive intestinal peptide, plasma angiotensin, serum factor, blood glucose raising hormone, thyroid stimulating hormone, stimulating hormone Thyroxine-releasing hormone, thyroid hormone, melanocyte hormone, melanocyte hormone-releasing hormone, melanocyte hormone-releasing-inhibiting hormone, corticotropin-like peptide, urase, cholecystokinin octapeptide, Cholestatin tetrapeptide, tremor beam variant, cholestradiin 12, cysteine pancreatic adenine, cholecystokinin, growth factor, substance P, female hormone, fatty acid vaporizing hormone, chorionic gonadotropin Hormones, Nerve Growth Hormone, Pancreatic Polypeptides, Breeding Nest Stimulating Substances, Gonadotropins, Growth Hormone, Growth Hormone Release Factor, Secretin, Hyla Edition, Serotonin, Fiber, Vitamins: Cell Growth Factor, Gland Vessel Relaxin, growth Class system, this paper -10- scale applicable to Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the back of the precautions to fill out this page)

A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (9) soma touted ins A and B, placental prolactin, thymosin, thymosin, thyroglobulin, traumatic acid, endothelial cell growth factor, Mollusc palpitation-stimulating neuropeptide, neurotensin, horse serum gonadotropin, brain hormone, neoadrenaline, vasopressin, estrogen, histamine, epidermal cell growth factor, parathyroid hormone, parathyroid hormone , Corticotropin releasing factor, adrenocortical hormone, PACAP, bradykinin, mimetic bradykinin peptide, proinsulin, p Γ ο 0 pi 0 me 1 a η 0 C 0 rti η, prostaglandins, Pro PTH, prolactin Hormone, prolactin-releasing hormone, prolactin-inhibiting hormone, Horigene, human menopausal gonadotropin, bombesine, mandibular hormones (MAXs), mineral corticosteroids, light-regulating hormones, methionamine and amidinide , 1-methyl-adrenine, melatonin, actin, androgen, diuretic hormone, fatty acid releasing hormone, renal enzyme, relaxing hormone, and follicle maturation hormone. Among the aforementioned physiologically active substances, substances that can be used to prevent or treat cerebral vasospasm and are preferred embodiments of the present invention include CGRP, MAXs, deferoxaiine, methyldehydrocortisol, nicorandil, nicaraben, magnesium sulfate, and actinide. Dactin D, 21-amino steroid, isoproterenol, tPA, niBodipine, cortisol, nicardipine, nifedipine, diltiazen, dilazp, teprothid, AA861, poppy age, 0KY1581, amyl nitrite, tetranitrate serilate, Isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, VIP, angiotensin, bradykinin, PACAP, SOD, catalase, bepridil, nadololol, felodipine, isradipine, varapami 1, atenolol, aetoprolol and propano lo 1 〇_ 1 1 _ This paper size applies Chinese National Standard (CNS) A4g (210X297 mm) (Please read the precautions on the back before filling this page) ------.-- -------- IT -------------- Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7__ V. Description of the Invention (《°) It has vasodilator effect Compounds, especially C6RP and MAXs are worth mentioning The carrier combination of the present invention, or a combination with other carriers capable of releasing physiologically active substances, can be implanted especially in the body, especially when implanted intrathecally, and can exert a significant effect, especially for preventing or treating cerebral blood vessels. Spasm. The abbreviations for MAXs used herein include the natural peptides (or proteins) derived from the sand fly Lut. 7 〇ν ia 1 η ne ί da 1 dis ^ (sequence identification number: 1 ) And its recombinant peptide; and GIL-modified mandibular hormone (see sequence identification number: 2 Lerner et al., J. Bio. Che Tong., Vol. 267 (2), pp. 106 2- 1 06 6, 1932 ) Wherein the N-terminus is modified with a sequence consisting of 3 amino acid residues GIL; and the like. Representative analogs include peptide digestion obtained according to the method shown by E.A. Lerner et al. (Same text), that is, to obtain a specially modified mandibular fusion protein, which is then digested with a protease such as factor Xa or thrombin. Representative examples are peptides (sequence identification number: 3) in which amino acid sequence residues GSIL are bonded to the sequence weave number: 1 mandible N-terminus and peptides (sequence identification number: 4) in which amino acid sequence The residue LVPRGSIL is bonded to it. MAXs also include those in which one or more amino acid residues of the amino acid sequence have been removed or replaced, and one or more amino acid residues have been added to the N- or C-terminus, and can be converted to C Terminal amino acid residues-LYs Ala Gly Lys or -Lys ALa- NH 2 〇 The industry can obtain the MAXs useful in the present invention by known liquid or solid phase peptide synthesis methods, or by recombinant methods, especially the above sequence listing Sequence identification number in the following: 1 to 4 amino acid sequence shown in the recombination method using one (Please read the precautions on the back before filling this page) ---------------. Order Φ. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (") A type of glycine sequence whose code is obtained by deleting one or more amino acid sequences of the amino group Acid residues, or the replacement of these residues with other amino acid residues "or the addition of other amino acid residues to the sequence generated by the sequence. The content of the physiologically active substance that can be contained in the soy sauce carrier of the present invention consisting of the aforementioned carrier and the selective use of adjuvant is not particularly limited, and the most appropriate content is based on the type of active substance used in the carrier and the method of application of the carrier. different. However, in general, based on the total weight of the drug, 1X10-12 to 30wU, preferably 1X10 to 5wtx physiologically active substance to the baby can be blended. The pharmaceutical preparation of the present invention can be prepared by mixing the aforementioned carrier components and physiologically active substances with the aforementioned content and using known formulation techniques. In these formulations, one or more optional additives commonly used in the industry can be blended. For example, dispersing adjusting agent, stabilizer, anti-gasification agent, wetting agent, adhesive, lubricant, etc. These additives are selected according to the dosage form of the pharmaceutical disc. The preparations thus prepared are usually lozenges, pills or capsules. But the preparations can also be liquids obtained by pulverizing the solid preparations prepared as above, so they can be used as injections and suspend the powder in a suitable fluid (such as sterile distilled water, physiological saline). Etc.) The resulting liquid. ♦ Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). In other respects, the aforementioned physiologically active substances, such as Ε.Α. Lerner and others, show that MAXs have blood vessels like CGRP Expansion effect. For example, the sequence identification number: 2 Mandibular hormone has an extremely interesting vasodilator effect, which is 80 to 100 times higher than CGRP. N-terminally modified mandibular hormone labeled with sequence identification number: 3 is known to have vasodilatory activity (especially Hongyan activity) and is about 10 times higher than sequence identification number: 2 (previously Onuma et al., Peptide Chemistry 1 9 9 3: Okada, pp.1 4 5- 1 48) is a particularly interesting -13- This paper size applies the Chinese National Standard (CN'S) A4 specification (210X 297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 _. _B7_ V. Peptide of the invention description (θ). However, the technical literature has not yet suggested that these MAXs can be used to prevent or treat cerebral vasospasm. Thus, according to the present invention, although cerebral vasospasm can be prevented or treated by a medical load that is preferably better than living body, in particular brain implantation including a prosthetic vehicle containing at least one MAXs, but also does not indicate that such a vehicle is not used And the use of MAXs to treat diseases. In other words, the present invention also provides a method for preventing or treating cerebral vasospasm, which comprises administering an effective amount of at least one MAXs to a patient who may have cerebral vasospasm or who has developed cerebral vasospasm. Such administration steps can be performed, for example, by administering an injection solution obtained by simply or dissolving or suspending at least one MAXs in sterile distilled water, physiological saline or buffer solution into a vein or artery; or by administering various inorganic salts as ions Strength modifiers or other excipients, such as dextrin, lactose, starch, etc., are added and formulated to prepare the resulting mixture. The administration time varies depending on the dosage form, the route of administration and the purpose (prevention or treatment), but it is usually administered immediately to the 10th day after the operation of the subarachnoid hemorrhage. As such, the present invention also provides, as another specific example, the preparation of a peony preparation for the prevention or treatment of cerebral vasospasm using at least one MAXs. The use of CGRP or MAXs-based medicinal preparations for intrathecal implantation has not been shown in the technical literature so far, and has advantages over neurosurgery such as Mae H. Shimizu 2): 1 3 1-1 3 9, 1 The remarkable advantages of the CGRP sterile aqueous solution shown in 9 9 4 in the cerebellum extension chain pool. -14- This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

A7 B7 V. Description of the invention (ο) Another important point is not only the combination of the aforementioned 翳 药 翳 剤 and CGRP or MAXs, but also the pharmaceutical preparation prepared by combining the aforementioned vasodilatory physiologically active substance with other carriers In the brain, effective prevention or treatment of cerebral vasospasm can be performed. Therefore, from this point of view, as mentioned above, the present invention also provides a method for preventing or treating cerebral vasospasm, which includes a wrap-around type tincture preparation containing certain carriers and containing a vasodilatory effect. The physiologically active substance is preferably implanted from at least one of CGRP and MAXs in a step in which cerebral vasospasm may occur or in patients with cerebral vasospasm. As another specific example of this method, the present invention also provides a physiologically active substance (or compound) having a vasodilating effect, preferably at least one selected from the group consisting of CGRP and MAXs, for preparing a sheath for preventing or treating cerebral vasospasm. Use of implantable pharmaceutical preparations. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The pharmaceutical preparations in this case can be pre-determined in effective long-term release dosage form, especially for parenteral administration, but are more suitable for the characteristics of the preparation Implanting it in vivo, especially in the brain, has a significant effect. When the medical preparation of the present invention is implanted in the brain, the active substance can be released for a long time and the dosage form can be maintained for 7 days or more. Most of the time, it is not only distributed at the administration site, but also dispersed throughout the brain. . Therefore, the active substance is not wasted, and the possibility of unnecessary effects on other parts is reduced. In addition, the system has the desired property that it will not harm the cells at the site of administration. It can release the active substance stably for a long time from 2 days to 2 weeks after administration, and then the base (carrier and adjuvant) is absorbed into the living body. When the preparation is in the form of a tablet for intrathecal implantation, it is hoped that it will be implanted in the subspinal membrane cavity and / or in the sulcus of the brain surface, so it will not use the Chinese National Standard (CNS) A4 specification (210X297 mm) for this paper size. Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China A7 _B7_ V. Description of Invention (β) Cerebrospinal fluid returns and flows. It is also hoped that the thickness of the preparation is 5 mm or less, so it can be implanted intrathecally without difficulty, and when the expansion coefficient of the lozenge is too large, it may damage the cells and the cells and / or tissues of the administration site, so the load needs to be adjusted. Agent and adjuvant ingredients so that the swelling volume is 200% or less. Those in the industry can easily determine the maximum amount of physiologically active substances that can be blended in these mineral-type hair-spraying preparations based on test tube tests or in vivo tests described later. The invention is further illustrated by the following specific examples, but these examples should not be considered as limiting the scope of the invention. Example 1 Preparation of wrap-around pharmaceutical preparation (P-1) 10 g of stearic acid was mixed with 19 g of hardened oil, 2.0 g of a 4% CGRP solution (equivalent to 8Bg CGRP) and 20 g of lactose and a mixed mixture were added, and 60 g of hydroxy Propyl cellulose. The mixture was fully mixed, and then compressed in a KBr shrinking machine (150 kg, 1 minute) to prepare a flat ingot (P-I) having a diameter of 13 mm. Example 2 Preparation of a wrapped pharmaceutical preparation (P-ιι) 20 g of stearic acid was mixed with 20 g of hardened oil, 2.5 g of a 4% CGRP solution (equivalent to 10 mg of CGRP) and 20 g of lactose and a mixed mixture were added, and 40 g of human was added Hydroxypropyl Lignin. The mixture was fully mixed and then compression molded using a COrrect compressor (Kikusui CLEAN PRESS) (6aim0 X 2ram). Example 3 Preparation of Continuation-Type Pharmaceutical Preparation (P-III) -16- (Please read the precautions on the back before filling out this page) -in β— —ΙΜ · ·---- tr ------- --- φ ------------ This paper is also applicable to Chinese National Standards (CNS > A4 size (210X297 mm)) Printed bags A7 of Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _B7_____ V. Invention Note (A) 15g palmitic acid is mixed with 15g bee pupae, 2.0g of 4% CGRP solution (equivalent to 8eg CGRP) and mixed mixture are added, and 70g of hydroxypropyl cellulose β mixture is added to mix thoroughly, and then compressed using 19K Compressor (Kinkisui CLEANPRESS) (6 nB 0 X 2 B m) Compression Molding "Example 4 Preparation of Peony Formula (P-IV) 10 g of palmitic acid was mixed with 10 g of hardened oil and 2.0 g of 4% was added CGRP solution (equivalent to 8mg CGRP) and 20g glucose and mixed mixture, and added 60g hydroxypropyl fervidin. The mixture was fully mixed, and then compression molded using a Correct 19K compressor (Kikusui CLEAN PRESS) (6am0 X 2u «) Example 5 Preparation of wrapped pharmaceutical preparation (PV) 10 g of stearic acid was mixed with 10 g of hardened oil, 2.5 g of 16% CGRP was added to dissolve (Equivalent to 40eg CGRP) and 20g of lactose and mixed mixture, and 60g of hydroxypropyl cellulose was added and the mixture was fully mixed, and then compressed using a Correct 19K compressor (Kikusui CLEAN PKESS) (6nm0 X2em) compression molding. Example 6, Wrapping Preparation of radiopharmaceutical preparation (P-VI) 10 g of stearic acid is mixed with 10 g of hardened oil, 2.5 g of a 10% CGRP solution (equivalent to 250 mg of CGRP) and 20 g of lactose and a mixed mixture are added, and 60 g of hydroxypropyl The cellulose base β mixture is fully mixed, and then molded using β-compressor (Kurisui CLEANPRESS) (6 mm X 2 mm) β-molding β Example 7 -17- This paper size applies the Chinese National Standard (CNS) Α4 specifications (210x297 male diamond) --------- Lu Zhuang --------- IT ----- (Please read the precautions on the back before filling this page) A7 B7 V. Invention Description (4) Preparation of wrap-around pharmaceutical preparation (P-VII) 10 g of stearic acid and 10 g of hardened oil are mixed, and 2.5 g of 6% labeled GSIL-modified mandibular hormone solution (3) is added. It is equivalent to 15 ng sequence identification number: 3) and 20 g of lactose and mixed mixture, and 60 g of hydroxypropyl cellulose is added. The mixture is fully mixed and then compression-molded using a Correct 19K compressor (Kikusui CLEAH PRESS) (6iaai?> X2bb), the molding ingot is pulverized and mixed and the same compressor (Kikusui CLEAN PRESS) (6nffl # X 2mn) is used. ) Moulded again. Example 8 Preparation of a wrapped drug delivery preparation (P-VIII) 10 g of stearic acid was mixed with 10 g of hardened oil, and 2.5 g of 1.0% was added. GSIL-modified-type mandible labeled with sequence identification number: 3 Solution (equivalent to 25 Bg sequence identification number: 3) and 20 g of lactose and a mixed mixture, and 60 g of hydroxypropyl wesperidin were added. The mixture is fully mixed and then compression-molded using a Correct 19K compressor (Kikusui CLEAN PRESS) (6nn0 X2nn). The molded ingot is pulverized and mixed and re-molded using the same compressor (Kikusui clean PRESS) (6nn0 X 2bi). . Example 9 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Preparation of wrapped pharmaceutical preparation (P-IX) 10 g stearic acid is mixed with 10 g hardened oil, added 2.5g 10% 檫 is shown as a sequence identification number: 3 GSIL-modified mandibular solution (equivalent to 250 Bg sequence identification number: 3) and 20 g lactose and mixed mixture, and 60 g hydroxypropyl starvation Victoria. The mixture is fully mixed and then compression-molded with a Correct 19K compressor (CLEAN PRESS) (6b · # X2bib), _ 1 8-This paper applies the Chinese National Standard (CNS) Bagu 1 grid (2i0X297 mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (q) Moulded ingots are powdered and mixed and re-molded using the same compressor (Kikusui CLEAN PRESS) (6bb # X 2bb). Example 10 Wrapping Preparation of radiopharmaceuticals (P-X) 15g of palmitic acid and I5g of beeswax were mixed, and 3.0g 0.4% of GSIL-modified mandibular solution labeled with sequence identification number: 3 (equivalent to 10 mg sequence identification) was added. No .: 3) and mix the mixture, and add 7Qg hydroxypropyl ferritin. The mixture was fully mixed and then compression-molded using a Correct 19K compressor (Kiyomizu CLEAN PRESS) (6nna0X2ni0.) Example 11 Preparation of a mine-type pharmaceutical preparation (P-XI) 2.0 g 0.4% CGRP solution (equivalent to 8Bg CGRP) 20g of lactose was mixed thoroughly, and 80g of hydroxypropylcellulose was added. The mixture was thoroughly mixed, and then placed in a KBr compressor (I5flfcg, 1 minute) to prepare a flat tablet with a diameter of 13β (P-XΙ) < »Example 12 Preparation of mounting thin pharmaceutical I (P-XII) 2.5 g 0.4% CGRP solution (equivalent to 10 ng CGRP) was fully mixed with 20 g of glucose, and 80 g of hydroxypropyl androsterin was added. Mix and place in a KBr compressor (150kg, 1 minute) to prepare a flat ingot (P-XII) with a diameter of 13 mm. Example 13 Preparation of a wrap-around pharmaceutical tincture (P-XIII) 2.5 g 0.4% CGRP solution (equivalent to lOing CGRP) and 13g poly (A-19- this paper size applies + national national standards (CNS > A4 ^ grid (210X297 mm)) (Please read the precautions on the back before filling in this page. A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Instructions (ι0-generation propionic acid-copolymerization-methyl methacrylate), excellent agent L_100 (trade name, available from German company LaBe) mixed, 87g of crystalline cellulose was added, the mixture was thoroughly mixed, and then placed in KBr Compressor (15Gkg, 1 minute) Preparation of diameter 1 3 BB lozenges (P-XI11) < »Example 14 Preparation of wrapped peony preparation (p-xiv) 17g stearic acid and 17g hydrogenated oil (hydrogenated castor oil ) Mix and add 2.0 g of 0.4% CGRP solution (equivalent to 8 mg of CGRP) and 0.39 g of poly (methacrylic copolymer-ethyl acrylate) excellent agent L30D-5.5 (trade name, available from Lane Company, Germany) And mixed the mixture, and added 668 crystalline fervidin. The mixture was thoroughly mixed, and then placed in a KBr compressor (150fkg / cra2, 1 minute) to prepare a 13bb diameter lozenge (P-XIV). Example 15 Wrapped pharmaceutical preparation ( P-XV) Preparation 100 g of 2% hyaluronic acid aqueous solution and 100 g of 2% euquinone E aqueous solution were reacted under stirring at room temperature for 2 hours. The reaction mixture was centrifuged at 3, QQ0 rpm for 10 minutes, the product was recovered and vacuum dried to obtain hyaluronic acid. Multi-ion complex of Youzhuo E. The obtained solid was differentiated and purified. Sieve to obtain a powder with a particle size of 150 ton or less. 100 powders are mixed with 0.75g of 0.496CGRP solution (equivalent to 3ag CGRP), and then compressed and molded using a Correct 19K compressor (Kikusui CLEAN PRESS) (6mB? IX2inm), and The molded ingot was pulverized and mixed and re-molded using the same compressor (Kikusui CLEAN PRESS) (6fflffli5 χ2ΒΠΒ). -2 0- —--------- ~-This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) (Please read the precautions on the back before filling out this page)- -------- © ^ ------ ΤΓ ----------- A7 B7 V. Description of the invention (< 9) Examples 16 to 20 Repeat the previous examples, special examples Procedures 14 and 15 but using the composition of the following Table 1. Table 1 Composition 16 (P-XVI) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics Example No. 17 (P-XVII) Preparation No. 18 (P -XVIII) 19 (P-XIX) 20 (P-XX) Crystalline vitamin (mg) 1600 1450 1300 2000 0 Hydrogenated oil Hydrogenated castor oil (Bg) 200 270 330 0 0 Stearic acid (mg) 200 270 330 0 0 Excellent agent® 120 110 100 300 300 L30D-5.5 (// 1) Excellent agent® L100 (g) 0 0 0 0.4 0.2 CMC · Na (g) 0 • 0 0 0 1.5 Lactose (g) 0 0 0 0 0.5 CGEP (mg) 0.2 0.2 0.2 0.2 0.2 H20 (ml) 0.2 0.2 0.2 0.2 0.2 Ethanol (ml) 0 0 0 5 0 -2 1- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page), 1T Staff of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (^) Example 2 1 to 3 4 Test tube release test of physiologically active substances Each 5inl Hartmann solution (obtained from Japan Cross Corporation) was placed in 15b1 tubes in a sterile manner. The following Pathway preparations were placed in these tubes in a non-calling manner: P-1, P-II, P-IV (Picture 1) P-V1I, P-VIII, P-IX (Figure 2) P-XΙ (Figure 3 ) P-XIIII, P-XIV (圔 4) P-XV (Figure 5) P-XVI, P-XVII, P-XIX (Figure 6) P-XVI II (Figure 7) P-XIX (Figure 8) Mixture At 37 ° C and 120 rpm, each sample was sampled for 1, 2, 3, 7, 11 and 14 days, and then the amount of physiologically active substances was measured by high performance liquid chromatography. The results are shown in the first to the first, respectively. 8 pictures (the relationship between the figure and the medicinal preparation is shown in the above brackets.) The numbers in the figure indicate the disintegration state of the tablet, and its meaning is as follows: disintegration state 1. No change 2. Observation of swelling 2 D% 3. Generation Small cracks · 4. Large cracks are generated 5. Disintegrate into small pieces -22- This paper size applies to China National Standard (CNS) A4 specifications (2ί〇 × 297 mm) (Please read the precautions on the back before filling this page) -------- I order one ---- Printed by A7 B7 of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (w) Example 3 δ Biological release test of physiologically active substances Using the tablets (P-III) obtained in Example 2 using three rabbits according to the method shown below In vivo testing of drug release effects. The results are shown in Figure 9. Test. 酴 Method: Color cut 黼 inplantation; ^ 皤 method rabbits (2.5-3.0 kg) were anesthetized with sodium amyl barbiturate and fixed on the face, cut open to expose the occipital membrane (dura mater), and drill to flatten the occipital bone. A wider dura mater is produced. Then cut the dura mater and arachnid to about 8mm in length. In the second example, the continuous-type pharmaceutical preparation tablet of Example 2 was implanted in two of the three heads, and the placebo tablet was implanted in the other head, and the dura, muscles, and skin cells were sutured. A small amount of antibiotic was administered to the incision site. Cerebrospinal fluid samples were taken from rabbits daily by the following method. The samples were analyzed for CGRP concentration in cerebrospinal fluid (UM) according to the following assay method. Cerebral chain fluid collection method Rabbits were fixed to the face after anesthesia with amyl barbiturn, and the occipital periosteum (dura mater) was exposed by incision. The occipital periosteum was cut and a cerebrospinal fluid sample was taken. How to analyze the substance concentration in the half bundle of the brain pedicle miscellaneous fluid. Concentration: The analysis is performed by the following radioimmunoassay analysis method. 4,000 parts of 4,000 cpn-labeled compound iodohistamine aldehyde ω) CGRP] were placed in a measuring tube, thereby preparing synthetic CGRP (obtained from Bachem) to prepare 1,200,1,5,10,50,100 each. , 500 and 100 fmol standard solutions. Add 100 # 1 antibody per portion (obtained by dissolving RPN 1841 (available from Amarsham) in 2nl diluted solution to 12.5 ml) and each 6 0 0 // 1 analysis buffer [50mM sodium gallate (PH7 .4), 0.3% bovine blood-23- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Inspection ^ ------ tr --------------- A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _ ^ _ B7___ V. Description of the Invention (^) Albumin, IObM EDTA] to 100 # 1 test samples In a standard solution or water test tube, cover the test tube cap, and place the mixture at 4 ° C for 5 days, 250 / zl glucosan / activated carbon solution [50nM sodium phosphate (PH 7 · 4), 0.25% gelatin, 1 ObM EDTA] was added to each mixture, and the resulting mixture was immediately centrifuged at 2,000 × g for 20 minutes. The y-counter was used to measure the 2D supernatant of the sediment for 0 seconds, and the concentration of physiologically active substance CGRP in the cerebrospinal fluid was analyzed based on the standard curve obtained from the standard substance solution. In addition, P-II tablets and rabbits other than 3 rabbits were used to perform the tablet disintegration in vivo test. At this time, the tablet was implanted into the brain injury in the aforementioned manner, and the state of tablet disintegration was observed through craniotomy. The results are shown below. The following values indicate the disintegration state of the tablets, and their meanings are the same as before. The collapsed state on the 1st and 5th days after implantation 2 2 4 From the results, it is understood that in vivo, even after 10 days after intrathecal implantation, the continuous cerebral vasospasm inhibitor of the present invention is still available Keep its dosage form. Examples 36 and 37 7 Vasodilation test (I) Vasodilation test: The tablets obtained in Examples 5 and 6 were also used, PV and P-VI, and tablets (solar tablets) without the physiologically active peptide CGRP were performed according to the following method . The P-V ingot results are shown in FIG. 10 and the P-VI ingots are shown in FIG. 11. An Wei's planing method as a placebo is a continuation type pharmaceutical preparation. The same as the wrapping type pharmaceutical preparation (PV) in Example 5 and the wrapping type pharmaceutical preparation (P-VI) in Example 6-2-This paper Standards are applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) ----------------- 1T ----- (Please read the precautions on the back before filling in this Page) A7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs _____5Z__ V. Description of the invention (w) Preparation method, but replacing CGRPe I with a hydroxypropyl carbamidine vitamin C. Test method according to the following method: ρ-v bond Experiments were performed with 8 rabbits and P-VI. The experiment was performed with 7 heads free of rabbits, weighing 2.5 to 3 fcg. (1) After taking X-ray photographs of the basilar artery of each rabbit, prepare a subarachnoid hemorrhage pattern according to a known method [DGVollner et al. Neurosurgery 28: 27-32 (1991)] (Day 0 (2) After 24 hours (day 1), each rabbit was anesthetized with sodium pentobarbital, and the occipital region was cut from the occipital bone along the midline to the first cervical spine. (3) Carefully remove the adhering to the occipital bone with a razor blade. A muscle of the cervical spine and occipital membrane without harming the veins. (〇The exposed occipital bone is scraped with a surgical drill to a thickness of 2 to 5 -m from the lower part. (5) The occipital membrane is then cut with a blade to a length of 8 (6) Use a pincer to place the lozenge into the subplaque plaque β (7) through this part. (7) After inserting the tablet, suture the occipital membrane with silk thread. U) Use Aron along the suture line Alpha (brand name) is further closed. (9) Subsequently, the muscle and skin are sutured with silk thread, and an appropriate amount of antibiotic is administered. (10) The caliber of the blood vessel is measured daily from the 5th day after the administration, and then (the 6th day) the blood vessel is Photographic measurement. Comparative Example Comparative test of Example 35 and Examples 36 and 37 As for the comparative example, according to the above 1) Known method by brain pool penetrating formula-2 5- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) '·----- I-II —Packing ---- --Order ----- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___B7__ V. Description of the Invention (4) The method of administering CGRP aqueous solution to 1 rabbit, In the same manner as in Example 35, the analysis and analysis of the CGRP concentration in the cerebrospinal sleep fluid over time were performed (mt0, and the results are shown in Fig. 12). As another comparative example, the CGRP aqueous solution or distilled water was administered in the exempt mode ( Two animals received CGRP aqueous solution and four animals received distilled water). Basal artery spasm was apparently observed in these rabbits after subarachnoid hemorrhage. This test was also performed using the cerebrovascular puncture method according to the known method of (1) above. The diameter of the blood vessel was measured in the same manner as in Examples 36 and 37. The results are shown in Figure U. Example 38 Vasodilation test (II) The ingot (P-VIII) obtained in Example 8 was used and did not include the serial number: 3 GSIL-modified mandibular hormone as a tablet of physiologically active peptides (comfort tablets), with examples 36 and 3 The vasodilation test was performed in the same manner as in Figure 7 (the results are shown in Figure 14). The comfort tablets were prepared in the same manner as in Example 8 except that GSIL-modified mandibular hormone was replaced with hydroxypropyl cellulose. Example 39 Living body of physiologically active substance Release test «Except for Example 35, this test was performed to obtain statistically more meaningful information. Repeat the procedure described in Example 35, but use 30 rabbits (" Normal J Day 1, Day 2, Day 3, 5 rabbits each on the 4th and 5th days), 1 (day 1), 2 (day 2), 3 (day 3), and 4 (days) after implantation (P-II) Spinal cord fluid (CSF) was collected from 5 animals every day on the 4th and 5th (day 5), and the CGRP degree of CSFs was analyzed. The results are shown in Figure 15. -26 " This paper size applies to China National Standard (CNS) A4 specification (210x297 male thin)-· I .------------------------------- (Please read the Note: Please fill in this page again.) A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the Invention (α) In the preceding paragraph, "normal" indicates an example of no implant (P-II). Example 40 Vital disappearance test of pharmaceutical preparations Vital test for disappearance of wound-type pharmaceutical preparations (ingots) in the brain Vulcanization using the tablets (P-II) obtained in Example 2 was performed by the following method "18 rabbits were used for this test (day 1 On the 2nd, 3rd, 4th, 5th, 10th, 1 month, 3 months and 6 months, two rabbits were used for surgery and the results are as follows. Head rabbits (2.5-3.0kg) were each anesthetized with sodium pentobarbital and fixed by the face. The occipital membrane (dura mater) was cut open to expose the dura mater with a drill. The dura mater and spider were then cut open. The film was about 8βπ long, and the ingot of Example 2 was implanted as a mineral-type medical preparation, and the dura mater, muscle, and skin were sutured, and an appropriate amount of antibiotics was injected into the incision site. 1 day, 2nd day, 3rd day, 4th day, 5th day, 10th day, 1 leap month, 3 months, 6 months, 2 rabbits each day, and undergoing craniotomy to expose the implant Observe the entry site with the naked eye. The evaluation criteria are as follows:-The tablet almost disappeared + almost half of the tablet disappeared + almost the entire tablet disappeared + + + Lost 27- The national standard (CNS) A4 size of this paper applies (210X297 mm) (Please read the precautions on the back before filling this page) --------------- ------ IT ---------------- B7 V. Explanation of the invention (4) Test result table Evaluation of the disappearance of several days after implantation B 1st 3 B 4th B + 5th + 10th + 1 month + 3 3 months + + 6 6 months + + + disappearance of the medicinal type pharmaceutical preparations (tablets) 0 «mandibular hormone ( Sequence identification number: 3) Cerebral vasospasm inhibition test 脳 rfn tuberculosis 动物 animal preparation of a rabbit death instance 41 (Please read the note on the back ^ before filling this page) Staff of the Central Standards Bureau of the Ministry of Economic Affairs Japanese white rabbits (male, weighing 2-3 kg) printed by Consumer Cooperatives under general anesthesia by injecting sodium pentobarbital through ear veins. After the rabbits are fixed and will not move, they will be disinfected with sterile ethanol around the perforating veins, and one will be fixed by itself Acupuncture through the vein, and then immediately connect the silicone expansion tube to a self-fixating needle (if the blood vessel is too detailed to use finger stimulation to expand the blood vessel), silicone One end of the tube is connected to a three-way cock, and the -28-size of this paper applies to the Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7. 5. Description of the invention (> 7 ) The two paths of the stopper are connected with 10nl syringes each containing normal saline, and the other path is connected with a 10 Bl syringe containing pentylbarbital. After the connection is completed, a saline injection needle is quickly injected into the vein, and then injected into the vein. Gibbarbital, and the amount became 75l »g / kg rabbit body weight. At this time, because the animal is anesthetized within one minute, it is necessary to fix the respiratory tract in advance to make the breathing clear. . Sui Jiexi insertion (Seldinger's ~ fr method) Incision of the femoral plaque to expose the arteries of the femoral area, using a guide wire to insert the catheter into the juvenile arteries from the exposed site under strong light fluoroscopy. Injecting 0.2 · 1 heparin to prevent Thrombosis occurs when the catheter is inserted. The rfn are all juxtaposition. The angiography is determined by the strong light transmission, and the head is quickly fixed to confirm the blood return, and 0.8ml imaging medium is injected under a certain pressure (2.3kg / cm2). Angiography was performed when 0.6ml was injected. Cerebral Acupuncture This procedure is performed at the same time as the test preparation blood is injected into the rabbit. The animal lies prone, with its head tilted downwards at an angle of 30 ° relative to the horizontal plane. confirm

Behind the occipital bone, confirm the first cervical spine and insert a 26G climbing butterfly needle with an angle of about 60 ° in between. When the needle touches the occipital bone, straighten the needle to 90 °. At this time, it was confirmed that cerebrospinal fluid was flowing out due to decompression. Fresh arterial blood was injected through this needle at a rate of 1 ml / Bin at a rate of 1 ml / kg rabbit body weight. After the injection, the back flow of cerebrospinal fluid was confirmed again, and the rabbit was allowed to stand without drying out the rabbit for 15 minutes or more. Cerebrovascular pictures of animals were taken 3 days after blood injection. -2 9- This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) (Please read the precautions on the back before filling this page) Packing. Order A7 B7 V. Description of the invention (4) Test cocoon : ≫ Hold multiple groups of rabbits, five in each group, as described above. Among them, when the basilar artery is divided into three equal parts from the vertebral artery junction, the midpoint diameter is measured, and the occurrence rate of spasticity is 18% or more. For the selected rabbits, a modified version of an aqueous solution of berberine labeled with a sequence identification number: 3 or a portion of distilled water was injected 3 days after the blood injection as a comparative example. Basal artery angiography was performed on each rabbit over time after administration, and the ratio of blood vessel diameter to blood vessel diameter before subarachnoid hemorrhage was studied. As for the model animals, rabbits weighing 2.5-3.Okg were used as follows. 8 heads were used in the modified mandibular administration group and 4 heads were used in the sterile distilled water administration group. The dose of modified mandibular hormone was 7 # g / kg rabbit body weight. The results are shown in Figure 16. As shown in FIG. 16, it was found that engraved to about 4 hours after the administration, the spasm in the modified-type mandibular solution aqueous administration group was significantly suppressed compared with the sterile water administration group. (Please read the precautions on the back before filling out this page) • Binding. Order Φ. Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics -30- The X degree of this paper applies to Chinese National Standards (CNS) (210X297 mm) Economy Printed by A7 B7, Consumer Cooperatives of the Ministry of Standards of the People's Republic of China 5. Description of the invention (0) Sequence table sequence identification number: 1 Sequence length: 6 3 Sequence category: Amino acid form: Linear molecule category: Peptide sequence

Cys Asp Ale Thr Cys Gin Phe Arg Lys Ala lie Asp Asp Cys Gin Lys 16 15 10 15

Gin Ala His His Ser Asn Val Leu Gin Thr Ser Val Gin Thr Thr Ala 32 20 25 3〇 Thr Phe Thr Ser Met Asp Thr Ser Gin Leu Pro Gly Asn Ser Val Phe 35 40 i} 5

Lys Glu Cys Met Lys Gin Lys Lys Lys Glu Phe Lys Ala Gly Lys 63 50 55 60 Sequence identification number: 2 Sequence length: 6 6 Sequence category: Amino acid Form: Linear Molecular category: Peptide «Sequence

Gly lie Leu Cys Asp Ala Thr * Cys Gin Phe Arg Lys Ala lie Asp Asp 16 '15 10 15

Cys Gin Lys Gin Ala His His Ser Asn Val Leu Gin Thr Ser Val Gin 32 20 25 30

Thr Thr Ala Thr Phe Thr Ser Met Asp Thr Ser Gin Leu Pro Gly Asn 48 35 45

Ser Val Phe Lys Glu Cys Ket Lys Gin Lys Lys Lys Glu Phe Lys Ala 6il 50 55 60

Gly Lys 66 65 -31- This paper uses Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) -Packing-, π:, ι§1_ι! 1ια : .. ngar A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs £ 7_ V. Description of the invention (#) Sequence identification number: 3 Sequence length: 6 7 Sequence category; Amino acid form: Linear molecule category: Peptide sequence

Gly Ser He Leu Cys Asp Ala Thr Cys Gin Phe Arg Lys Ala He Asp 16 15 10 15

Asp Cys Gin Lys Gin Ala His His Ser Asn Val Leu Gin Thr Ser Val 32 20 25 3〇

Gin Thr Thr Ala Thr Phe Thr Ser Met Asp Thr Ser Gin Leu Pro Gly 48 35 U0 45

Asn Ser Val Phe .Lys Glu Cys Met'Lys Gin Lys Lys Lys Glu Phe Lys 64 50 55 60

Ala Gly Lys 67 65 Sequence identification number: 4 Sequence length: 71 Sequence class: Amino acid Although Form: Linear Molecular class: Peptide Sequence

Leu Val Pro Arg Gly Sep lie Leu Cys Asp Ala Thr Cys Gin Phe Arg 16 5 10 15

Lys Ala He Asp Asp Cys Gin Lys Gin Ala His His Ser Asn Val Leu 32 20 25 30

Gin Thr Ser Val Gin Thr Thr Ala Thr Phe Thr Ser Met Asp Thr Ser M8 35 40 45

Gin Leu Pro Gly Asn Ser Val Phe Lys Glu Cys Met Lys Gin Lys Lys 64 50 25 6〇

Lys Glu Phe Lys Ala Gly Lys 71, 65 ,, 70 _: __ This paper size applies to Chinese national standards (CNS> A4 size (210X297mm) -32- I-1 II, 1. Binding! W (Please read the back first (Notes for filling in this page)

Claims (1)

A8 B8 C8 D8 Jil! __ U ί Patent Application No. 83110658 "Employee Consumer Cooperative Cooperative of the Central Standardization Bureau of the Ministry of Physiology and Economy 1 · A substance substance selects enoic acid as a selective element, prime 2. Rushen 僳 僳 3. Russ load ％% combination 4. Russ load ％% 5. Russ load 聚% profit range: contains Effective amounts of implanted carriers in vivo include free fats and ester derivatives such as free cellulose, hydroxypropylmethyl and crystalline fibers. Patented scope refers to the sheath. Patented scoped agents include 10 to fats or oils or substances. The total weight is from 10 to _ for patent coverage agents, and 10 to acrylates for pharmaceutical patent coverage agents are commonly used. The active substance is a type of peony drug composition patent (revised on December 2, 1985). Pharmaceutical composition for sustainable release of physiological activity, characterized in that the physiological activity is a combination of a physiologically active polymer with a weight of 10 to 90%, and at least one oil, wax, fatty acid, amidine and polypropylene, co-ribs, Among them cellulose polymers. Ether derivatives such as hydroxypropylcellulose, methylgastrovinyl cellulose, hydroxyethylgastrovin and carboxymethylpanvidin. The pharmaceutical composition according to item 1, characterized in that the pharmaceutical composition according to item 1 or 2 is 90% by weight of a cellulose acid derivative wax and 1 to 30% by weight of a fatty acid. The pharmaceutical composition of item 1 or 2 90% by weight of the total weight of the starvedrin ether derivative pharmaceutical composition. The pharmaceutical composition of item 1 or 2 (please read the precautions on the reverse side before filling out this page) The body of the body is 1 棻 30 double image, the medicine is 1 徴 4 棻, and the special badge is 9 0% by weight of crystalline vitamin D, 0.01 to 10, 10 weight is based on the total weight of pharmaceutical preparations. This paper size applies to Chinese national standards (CNS> A4 specifications (210X297 mm)-order _ A8 B8 C8 D8 Jil! __ U The scope of patent application No. 83110658 "Employee Consumer Cooperative of the Central Bureau of Standards, Ministry of Physiology and Economy, Qiu System..M. Please. Members expressly, whether to modify the original substance of this case and apply for a special application. Selective acid is a selective element, such as 2. Intended to be loaded 3. Intended to be loaded in% Combination 4. Intended to be loaded in% 5. Intended to be loaded to% The range of profit: containing an effective amount of in vivo implantation The included carriers include free fatty cellulose and ester derivatives such as free cellulose, hydroxypropylmethyl, and crystalline fibers. The scope of patents refers to the sheath. The scope of patents includes 10 to the total weight of fats or oils or substances. Agents include 10 to _ "Acrylic ester, active substance release type peony composition" patent case (amended on December 2, 1985) A physiologically active substance and a sustainable release of a physiologically active pharmaceutical composition, which is characterized by its physiological activity 10-90 A combination of starvin polymer with at least one oil, wax, fatty acid, hydrazone and polypropylene, co-ribs component, among them cellulose polymer. Ether derivatives such as hydroxypropyl cellulose, methyl-divitamin , Hydroxyethyl followin and carboxymethyl pavidin. The pharmaceutical composition of item 1 is characterized in that the pharmaceutical composition of item 1 or 2 is 90% by weight cellulose acid derivative wax and 1 to 30% by weight fatty acid. The pharmaceutical composition of item 1 or 2 is 90% by weight based on the total weight of the starvedrin ether derivative drug composition. The pharmaceutical composition of item 1 or 2 (please read the precautions on the back before filling this page) } The body has a badge of 1 棻 30, with a paeonia lactiflora, and its weight is 1 棻 4Θ. Its special emblem is 90% by weight of crystalline vitamin D, 0.01 to 10, and the most weight is based on the total weight of the pharmaceutical preparation. This paper size applies to Chinese national standards (CNS> A4 specifications (210X297 (Mm)-Order_ A8 Βδ, C8 D8 6. Application scope of patent 6. If the medical composition of scope 1 or 2 of the patent application, the special emblem is that the physiologically active substance is a physiologically active peptide. 7. If applying The pharmaceutical composition according to item 6 of the patent, wherein the physiologically active peptide is a calcitonin (Calc if onin) gene-related peptide (CGRP). 0. For the pharmaceutical composition according to item 6 of the application, The specific activity is that any one of fflaxadilans (MAXs) develops the physiological activity. ° 9. A pharmaceutical composition for implantation in vivo that contains an effective amount of a physiologically active substance and can continuously release the physiologically active substance, wherein the physiologically active substance is one or more compounds selected from CGRP and MAXs, and a physiologically active substance The carrier includes about 50% by weight hyaluronic acid and about 50% by weight cationic polyacrylic acid derivative, based on the total weight of the pharmaceutical preparation. -----— 丨 —Θ 袭 ------ 1T ------ Φ (Please read the precautions on the back before filling out this page) Printed Paper Sizes by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Applicable to China National Standard (CNS) A4 specification (210X297 mm)