JPH0436233A - Sustained release preparation containing physiologically active substance and decomposable and absorbable in living body - Google Patents

Abstract

PURPOSE:To obtain the subject drug preparation having high uptake ratio and loading ratio of drug, exhibiting suppressed burst at the initial stage of release and capable of slowly releasing the drug over a long period by including a physiologically active substance into a small sphere of a water-soluble polymer and coating the sphere with a polymer decomposable and absorbable in living body. CONSTITUTION:A small sphere having particle size of 0.01-200mum is produced from an aqueous solution of a water-soluble polymeric substance (e.g. sodium polyacrylate, PVA, CMC, gelatin and carrageenan) containing a physiologically active substance by spray-drying, coacervation, fluidized bed process, drying in liquid, freeze-drying, etc. The small sphere is encapsulated with a polymer decomposable and absorbable in living body (e.g. polyglycolic acid, polylactic acid and polyamino acid) by drying in liquid or spray-drying to obtain the objective sustained release preparation having particle size of 0.01-300mum.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides lI:, jl! In vivo absorbable sustained release formulations I containing active substances: Relating to.

[Conventional technology]

In contrast to conventional drug administration methods, such as single-dose injections or intravenous injections, composite materials of drugs and polymers can be directly inserted into the body, or local injections such as microcapsules and microspheres can be used. The administration method aims to increase drug efficacy and suppress side effects by slow release of the drug. Research on the sustained release or connectivity of such drugs, i.e., drug delivery systems (D
Research on DS) has been actively progressing in recent years. As a drug-retaining matrix in the DDS, biodegradable and absorbable polymers such as gelatin and polylactic acid are often used, or as microencapsulation matrices. This gelatin is chemically crosslinked using a crosslinking agent such as glutaraldehyde to form a formulation. On the other hand, since polylactic acid and milk Wa/glycolic acid copolymer are hydrophobic polymers, they have good affinity with hydrophobic drugs such as steroid hormones, and are often used as matrices for sustained-release preparations. There is. However, in the case of gelatin, toxicity issues such as the cross-linking agent glutaraldehyde have not been clarified, and the sustained release period when using a gelatin matrix is relatively short at about 1'A. It is between. On the other hand, the degradability and sustained release properties of polylactic acid matrix can be controlled relatively well by changing its molecular weight and copolymer composition ratio, but as mentioned above, it is hydrophobic. It has poor affinity with water-soluble drugs, and preparations obtained by microsphere formation have a severe initial burst and have poor sustained release properties.

In view of this, the following formulation is known as an attempt to achieve sustained release of a water-soluble drug for about one month. In JP-A No. 60-100516, a W10 type emulsion is prepared in which the inner water layer is a liquid containing a water-soluble drug and a drug-retaining substance, and the oil layer is a solution containing a polymeric substance. A method for producing sustained release microcapsules for water-soluble drugs is described, which is characterized in that the emulsion is thickened or solidified to about 5000cP or more and then subjected to -t3 drying in water. Because it is made up of a drug-retaining substance and a polylactic acid-based capsule wall,
It is interesting that the burst phenomenon at the initial stage of release has been improved and sustained release for about one month has been obtained.6However, as described in the contents of this Mei-aS, it is difficult to incorporate the drug into microcapsules or microcapsules. Low uptake rate, 71 even with high tth
．． It is about 5%. Physiologically active substances are not only expensive but also poisonous to living organisms, so a low drug uptake rate is not only uneconomical but also requires labor to recover unincorporated substances. Furthermore, it is a national problem to increase the loading rate of drugs that are electrolytic in both water and organic solvents, such as the anti-malignant tumor drug cysubratin.

[RuJM points to be solved by the invention] These known methods provide a DDS system that achieves certain results as described above, but they do not allow for increasing the rate of drug incorporation into the formulation. There are no r'jJM points.

Therefore, the present inventor has developed a drug that is relatively easy to prepare and can increase the drug uptake rate in the preparation to over 80%, and that is stable over a high range of 1.1m to 1 year. After intensive investigation into a formulation method that would provide sustained release, we found that after preparing microspheres made of a physiologically active substance and a water-soluble polymer, these microspheres were further coated with a hydrophobic biodegradable and absorbable polymer. The present invention was based on the discovery that by encapsulation, it was possible to increase the uptake rate and loading rate of the drug, and also to obtain a sustained release preparation that suppressed the initial release burst and had sustained release properties over a long period of time. completed.

The incorporation rate of the physiologically active substance used into the microcapsules was as high as 80% or more, and in an in vitro dissolution test (pH 74, in a phosphate buffer solution, 37°C), after 24 hours. A biodegradable and absorbable material with an average particle diameter of 0.01 to 300 μm that allows sustained release at a constant release amount over a long period of time, with the elution amount of physiologically active substances controlled to 40% or less of its content. It provides a release formulation.

Raw J21 according to the present invention! Active substances are hydrophilic,
Preferred drugs include drugs with a low oil-water partitioning ratio, but they may also be compatible with oil-water. Also, is it difficult to tolerate both water and organic solvents? Examples of such drugs include hydrophilic or sparingly soluble anticancer drugs, antibiotics, peptides and proteins that modulate physiological activity, antipyretics, sedatives, anti-inflammatory drugs, and antipyretic agents. antihypertensive agent, ffl cough agent, antiepileptic agent, antihistamine, antihypertensive diuretic-rurinary disease treatment agent, muscle relaxant, anti-GFH agent, antidepressant, antiallergic agent 1
Examples include cardiac i7-arrhythmia therapeutic agents, vasodilators, anticoagulants, l antagonists, hemostatic agents, antituberculous agents, and hormonal agents.

The water-soluble polymeric substances used as physiologically active substance carriers used in the present invention include synthetic ones such as sodium polyacrylate, polyethyleneimine, polyvinyl alcohol,
Polyvinyl methyl ether.

Examples include polyethylene oxide and polyvinylpyrrolidone. In addition, examples of semi-synthetic products include carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropylcellulose, and cellulose acetate phthalate. Furthermore, natural water-soluble polymers include gelatin, collagen, casein,
Sodium alginate, propyl glycol alginate, carrageenan, 7-celleran, pectin.

Gum arabic, guar gum, xanthan gum, gum tragacanth, dextran, albumin, agar.

Introduction, and several minute derivatives. These water-soluble polymeric substances may be of one kind, and preferably two types, such as tin, albumin, dextran, or starch. In addition, when used for oral administration or rectal administration such as during menstruation, non-degradable and absorbable substances may be used. Preferred examples of 4R include polyvinyl alcohol and hydroxypropyl cellulose.

In addition, the biodegradable and absorbable polymeric substances used in the present invention for further coating the microparticles with the water-soluble polymeric substance containing a physiologically active substance include polyglycolic acid, polylactic acid, lactic acid/glycol acid copolymer, poly-
Micaprolactone.

Lactic acid/caprolactone copolymer, polydepsipeptide,
Polyamino acids, polyalkylcyanoacrylates, polyacid hydrates, polyorthoesters, polyorganophosphazenes, polyorthocarbonates, polyphosphates, chitin, poly-β-hydroxybutyrate, hydroxybutyrate/valerate copolymers Alternatively, a polyethylene glycol/lactic acid copolymer or the like is preferable.One type of these biodegradable and absorbable polymers may be used, and a polylactic acid-based polymer is preferable from the viewpoint of certain in-body safety.

The molecular weight of these polymer substances used in the present invention is not particularly limited, but! l weight average molecule i 2,0
The range is preferably from 00 to 1 million.

A more preferable molecular weight range is from 3,000 to 200,000.

The formulation of the present invention contains a water-soluble polymer matrix as a drug-retaining substance and other substances commonly used in pharmaceutical formulations, such as solid diluents, carriers, binders, and excipients, in addition to the above-mentioned physiologically active substances. and adjuvants may be included.

The loading rate (content) of the physiologically active substance in the sustained release preparation of the present invention varies depending on the type of drug, the desired pharmacological effect, and the sustained release period, but is approximately 0.1% to approximately 80% (
W/W), preferably a range of 1% to 50% (W/W). In addition, the size of sustained-release preparations ranges appropriately from a few nanometers to several hundred microns, allowing intravenous injection.

6. The biodegradable and absorbable bioactive substance containing bioactive substance of the present invention can be made and used depending on TJ, such as lymphotropism, administration to China, or accumulation in endothelial tissues such as the liver, lung, and pancreas. The sustained-release preparation is manufactured through a two-step process. First, as a first step, microspheres of a water-soluble polymeric substance containing a physiologically active substance are produced, and these microspheres are prepared using known methods such as spray drying, core cell basin method, fluid bed method, and submerged drying. It is manufactured by the freeze-drying method, freeze-drying method, etc. These manufacturing methods can be selected depending on the intended use of the sustained-release preparation, but the spray-drying method is the most preferable for pre-treatment.When manufacturing drug-containing water-soluble polymer microspheres using the spray-drying method, The size of the microspheres can be determined depending on the concentration of the water-soluble polymer solution used and the spray drying conditions. It can be prepared as follows.

In addition, when producing drug-containing water-soluble polymer microspheres by drying in oil, a W10 type emulsion is formed by dissolving a solution of the drug and water-soluble polymer in water in an oil such as silicone oil. Thereafter, the probe microspheres may be chemically cross-linked at low temperature using, for example, glutaraldehyde or succinic anhydride.

Furthermore, when using water-soluble polymers such as albumin,
Microspheres can also be obtained by heating to about 100°C and thermally denaturing them. In the second step, the water-soluble polymer microspheres containing the drug thus obtained are further processed into biodegradable and absorbable polymer microspheres. It is coated with molecules, and in this case as well, it can be manufactured by spray drying or submerged drying. Specifically, organic solvents that do not dissolve the water-soluble polymer microspheres containing the drug mentioned above but dissolve biodegradable and absorbable polymers, such as chloroform, acetonitrile, or chloride when using polylactic acid-based polymers, are used. A solution in which water-soluble polymer microspheres containing medicine are dispersed in an organic solvent such as methylene is encapsulated using a spray dryer, or
It is obtained by forming an O10 emulsion and encapsulating it by an in-liquid drying method. Here, the dispersion medium used when encapsulating by the in-liquid drying method is substantially incompatible with organic solvents such as methylene chloride and acetonitrile, which are solvents for polylactic acid polymers, and is removed after formulation. For example, silicone oil, liquid paraffin, vegetable oils and fats such as nut oil, sesame oil, castor oil, and corn oil, and organic solvents such as toluene, xylene, and hexane can be used. Also, water can be used instead of these oils, but this is not preferable because the water-soluble physiologically active substances contained in the water-soluble polymer microspheres will dissolve into the water in the dispersion medium during drying in the liquid. As water is not used as a dispersion medium during encapsulation,
The method for producing sustained-release preparations of the present invention provides an extremely high uptake rate of physiologically active substances.

The sustained release drug containing a physiologically active substance obtained by the present invention is an injection preparation for medical or veterinary use, and an IY:0 preparation.

It is applied to medicinal absorbents, dental preparations, suppositories, nasal administration agents, buccal administration agents, intraocular administration agents, etc.

〔Effect of the invention〕

According to the present invention, the biodegradable and absorbable sustained-release agent containing the physiologically active substance ↑5 IL has a drug incorporation rate into the sustained-release agent of 8.
Not only can the release rate be improved to 0% or more, but also the initial burst of elution from the preparation can be controlled, and sustained release can be provided over a long period of time, from one week or more to one year.

The present invention will be explained in detail by giving examples below.

Example 1 1g of tetracycline was prepared by heating to prepare 5%
Tetracycline-containing gelatin microspheres (average particle size of about 5 ml) were prepared by dissolving the gelatin in 100 ml of an aqueous gelatin solution and drying it by spraying using Parvis Mini Spray Model A-32 manufactured by Yamato Kagaku. These microspheres were prepared in advance using milk #/glycol copolymer (composition ratio 80/20m01% 1-fold average molecular weight
12,000) in 10% acetonitrile by stirring with a star 5-. This solution was poured into 300 mL of liquid paraffin containing 1% Span 80 (sorbitan monooleate) prepared in advance under stirring to form an emulsion, and the acetonitrile was evaporated under continuous stirring all day and night.

Thereafter, biodegradable and absorbable microcapsules containing tetracycline with an average particle size of about 10 μm were produced by centrifugation, fractionation, washing with hexane, and drying.

After dissolving 2011 g of these microcapsules in 20 ml of methylene chloride solution, it was incubated with 2 hl of distilled water for 20 minutes.
Tetracycline was extracted by + shaking and quantified by ultraviolet absorption spectrum (UV), and the uptake rate was determined as the ratio of the drug incorporated into the microcapsules to the charged amount, and was found to be approximately 98%. in
VitrO elution experiments involve plating a predetermined amount of microcapsules into
The test was carried out in a phosphate buffered H7.4 solution at 37° C. in a constant temperature bath with a shaker, and the moisture content of the drug was evaluated by measuring p UV.

The elution amount of IH eye was about 20%, showing sustained release in a constant amount for 14 days.

Comparative Example 1 20 prepared by heating 0.1 g of tetracycline
% gelatin solution dissolved in 10 ml of aqueous solution.

Pre-prepared lactic acid/glycolic acid copolymer (M acid ratio 80/20+no 1% 1 weight average molecule m 12,0
A W10 emulsion is formed by adding 20n+1 of a 20% methylene chloride solution of 00> and ultrasonication (30 KHz, 100 W, 1 minute), and then immediately cooled with water to solidify the gelatin layer. This product was dropped into 200 ml of a 0.2% polyvinyl alcohol aqueous solution that had been previously ice-cooled, and dispersed for about 10 seconds using a homogenizer to prepare a W10/W emulsion.

This is immediately transferred to a rotary evaporator to remove methylene chloride under ice cooling. After that, the organic solvent is removed by heating, and the microcapsules are separated by filtration with a glass filter and washed! I built two.

When the incorporation rate was determined using the same method as in Example 1,
It was about 60%.

Furthermore, when a 1nvitro molten field experiment was conducted in the same manner as in Example 1, approximately 50% elution was observed on the first day.

After that, sustained release was observed for 10 days.

Example 2 As a coating material for tetracycline-containing gelatin micro/7% spheres! Tetracycline-containing sustained-release microcapsules were manufactured under exactly the same conditions as in Example 1, except that a lactic acid/glycolic acid copolymer (composition ratio 80/20 mo1%) with an Sk average molecular weight of 26,000 was used. The uptake rate was determined by the same method as in Example 1 and was approximately 99%. In addition, a 1n vitro elution experiment was conducted in the same manner as in Example 1. The elution amount on the first day was approximately 16%, and a sustained release was observed for approximately 1 month thereafter.

Example 3 1g1I was prepared from 200μ of cisplatin by heating.
After dissolving in 200 ml of % gelatin aqueous solution, 14 cisplatin-containing gelatin microspheres (average particle size of about 2 μff+) were prepared by spray drying. Polylactic acid microcapsules were produced in the same manner as in Example 1, except that poly-D, L-lactic acid (weight average molecular weight: 9,600) was used as the microspheres. The uptake rate was determined using the same method as in Example 1 (quantification was done by atomic absorption) and was approximately 97%. In addition, an in vitro elution experiment was conducted using the same method as in Example 1, and quantification was performed using atomic absorption spectrometry.
5%, and then showed a certain amount of gradual decline for about 2 weeks.

Comparative Example 2 Microcapsules were prepared from 200 mg of cisplatin in the same manner as in Comparative Example 1. "XX Construction 1 The uptake rate was determined using the same method and was approximately 38%.

In addition, an in vitro elution experiment was conducted in the same manner as in Example 3, and quantification was performed using atomic absorption spectrometry.
80%, 90% on the second day, and 100% after about 4 days.
% release was observed.

Example 4 After dissolving 200 mg of leuprolide acetate, which is a luteinizing hormone-releasing hormone LHRH agonist, in 50+ nl of a 4% aqueous gelatin solution prepared by heating, gelatin microspheres containing leuprolide acetate (average Particle size approximately IO μm) was prepared as 'p4.

Microcapsules were produced from these microspheres in the same manner as in Example 1. Uptake rate was carried out in the same manner as in Example 1 (however, quantification was done using HP I).

C) was found to be approximately 93%.

These microcapsules were dispersed in physiological saline and administered subcutaneously to adult female rats weighing approximately 300 g (LHRH dosage: 12 mg/kg). When the atrophy of the Q organ of the internal reproductive system due to desensitization was observed, the effect persisted for about 50 days.

Comparative Example 3 Microcapsules were produced using 200 mg of leuprolide acetate in the same manner as in Comparative Example 1. The uptake rate was determined using the same method as in Example 4 and was approximately 62%.

Example 5 After dissolving 200 mg of human insulin in 200 ml of a 3% gelatin 0.1N HCl aqueous solution prepared in advance, gelatin microspheres containing insulin were prepared using a spray drying method. Microcapsules II2 were prepared by the same method.

Uptake rate was determined by the same method as in Example 1 (quantification was performed using an enzyme method)
The result was approximately 94%. In addition, when an in virro elution experiment was conducted in the same manner as in Example 1,
29% at L1 on day 1, then reduced sustained release at a fixed dose for about 4 weeks.

Comparative Example 4 Microcapsules were produced using 200 mg of human insulin in the same manner as in Comparative Example]. The uptake rate was determined using the same method as in Example 5 and was approximately 55%.

Example 6 After dissolving 10,000 units of calcitonin in 100 nl of a 4% gelatin aqueous solution prepared in advance,
,,'J Shire dry method to make gelatia microspheres containing calcitoyut @! Manufactured. Microcapsules were formed from the microspheres using the same method as in Example 1. As for calcitonin activity, no decrease in the activity was observed according to the measurement results based on the serum calcium lowering effect. The uptake rate using the same method as in Example 1 was about 96%. (Quantitative) I
PLC) In addition, in vitro using the same method as in Example 1
A tro elution experiment was conducted.

It showed sustained release of about 18% on the first day and a constant amount for about 4 weeks thereafter.

Comparative Example 5 10,000 units of calcitonin were prepared into microcapsules by the same method as in Comparative Example 1. The uptake rate was determined using the same method as in Example 6 and was approximately 47%.

Example 7 After dissolving 1 x 10" units of human interferon α in 100 ml of a 2% aqueous gelatin solution prepared in advance, interferon-containing gelatin microspheres were prepared by spray drying. These microspheres were used in Examples] Microcapsules were manufactured by the same method as in Example 1.The uptake rate was determined by enzyme antibody method and was approximately 93%.In addition, an in vitro elution experiment was conducted using the same method as in Example 1, and the activity remained for approximately 4 weeks. It lasted.

Comparative Example 6 IXIO' units of human interferon α were added to Comparative Example 1.
Microcapsules were manufactured by the same method. When the uptake rate was determined using the same method as in Example 7, it was approximately 50%.

Example 8 2XIO″ interleukin IJ (IL-If
) in 5% gelatin water solution #t200m
IL-U containing gelatin microspheres were prepared by spray drying. The microspheres were subjected to HM microcapsules using the same method as in Example 1. The obtained microcapsules were administered into the blood of mice, and the blood levels of IL-II and Ctr, L-2, which are cell lines dependent on L-II, were measured over a period of about 2 weeks. High concentrations of more than 1×10′ units/ml were detected. Moreover, the incorporation rate into the microcapsules was about 90%.

Comparative Example 7 Microcapsules were prepared using 2×10′ units of TL-[ in the same manner as in Comparative Example 1. The uptake rate was determined using the same method as in Example 8 and was approximately 53%.

Example 9 After dissolving 5 x 10' units of thrombolytic agent (TPA) in 100 ml of a 3% gelatin aqueous solution prepared in advance, ``1'' P A -containing gelatin microspheres were prepared by a spray drying method. Microcapsules were produced from these microspheres in the same manner as in Example 1. The incorporation of '1' PΔ into this microcapsule was approximately 92%. An in vitro elution test was performed and enzyme activity was measured using a fibrin plate method.

The activity lasted for about 4 weeks.

Comparative Example 8 Microcapsules were prepared using 5 x 10' units of TPA in the same manner as in Comparative Example 1. The uptake rate was determined using the same method as in Example 9 and was approximately 32%.

Example 10 After dissolving 100+ mg of bovine somatotropin in 100 ml of a pre-prepared 2% aqueous gelatin solution.

Somatotropin-containing gelatin microspheres were all-Wed by a spray drying method. Microcapsules were produced from these microspheres in the same manner as in Example 1. The obtained microcapsules were injected under pressure into a cow, and somatotropin in the plasma was measured by radioimmunoassay, and somatotropin was detected for about 40 days. Moreover, the uptake rate was about 93%.

Comparative Example 9 Microcapsules were prepared using 100 mH of bovine tuma 1-tropin in the same manner as in Comparative Example 1. The uptake rate was determined using the same method as in Example IO and was approximately 40%.

Example 11 2g of diclofenac sodium (Voltaren) in pre-prepared 2% polyvinyl alcohol/L7(1)
VA) (Polymerization degree 500. Saponification degree 99.5 mo/l/%)
After dissolving in 100 ml of aqueous solution, Voltaren-containing PVA microspheres were prepared by a spray drying method.

The microspheres were coated with voltacin under exactly the same conditions as in Example 1, except that lactic acid/glycolic acid copolymer (ffl composition ratio 70/:10 + NO 1% 1 weight average molecular weight approximately 3,500) was used. Sustained-release microcapsules were manufactured. The uptake rate of Voltaren into the microcapsules was measured using UV and was found to be approximately 99%. In addition, when this microcapsule was formulated into a physiological formulation using cacao oil and a dissolution test was conducted, zero release was observed for 48 hours.

Claims (1)

[Claims] 1) After creating microspheres from an aqueous solution of a water-soluble polymeric substance containing a physiologically active substance, the microspheres are further coated with a hydrophobic polymeric substance that is biodegradable and absorbable. encapsulated sustained release formulation. 2) The physiologically active substance is an antibiotic, an antibacterial drug, an anticancer drug, an antipyretic analgesic, an antitussive expectorant, an antidepressant, a muscle relaxant, an antiulcer agent, an antiallergic agent, an antihypertensive diuretic, a diabetic agent, a cardiotonic agent, Claim No. 1 is a vasodilator, an antiarrhythmia agent, an anticoagulant, a hemostatic agent, a narcotic antagonist, an antituberculous agent, a hormonal agent, an immunostimulant, an antiepileptic agent, an antihistamine, or a peptide and protein drug. The sustained release preparation according to item 1. 3) Water-soluble polymeric substances include sodium polyacrylate, polyethyleneimine, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, chitosan, hydroxypropylcellulose, cellulose acetate phthalate, gelatin,
Collagen, casein, sodium alginate, propylene glycol alginate, ester, carrageenan, farcellan, pectin, gum arabic, guar gum, xanthan gum, gum tragando, dextran, albumin, agar, lees, and lees derivatives as described in claim 1 sustained release formulation. 4) Biodegradable and absorbable polymeric substances include polyglycolic acid, polylactic acid, lactic acid/glycolic acid copolymer, poly-ε-caprolactone, lactic acid/ε-caprolactone copolymer, polydepsipeptide, polyamino acid, polyalkyl Cyanoacrylate, polyanhydride, polyorthoester, polyorganoposphazene, polyorthocarbonate, polyphosphate ester, chitin, poly-β-hydroxybutyrate, hydroxybutyrate/valerate copolymer, and polyethylene glycol/ The sustained release preparation according to claim 1, which is a lactic acid copolymer or the like. 5) The scope of the present invention is characterized in that microspheres of a water-soluble polymeric substance containing a physiologically active substance are produced by a spray drying method, a coacervation method, a fluid bed method, an in-liquid drying method, a freeze-drying method, etc. The sustained release preparation according to item 1. 6) Claim 1, characterized in that the physiologically active substance-containing water-soluble polymeric substance produced according to Claim 5 has a microsphere size in the range of 0.01 to 200 μm. sustained release formulation. 7) The microspheres of the water-soluble polymer containing a physiologically active substance produced according to claim 5 are encapsulated using a biodegradable and absorbable polymer by a submerged drying method or a spray drying method. The sustained release preparation according to claim 1, characterized in that: 8) The sustained-release preparation according to claim 1, wherein the sustained-release preparation produced according to claim 7 has a size in the range of 0.01 to 300 μm. 9) Claim 7 is characterized in that water is not used when the biodegradable and absorbable polymer is encapsulated in the water-soluble polymer microspheres containing a physiologically active substance by an in-liquid drying method. A sustained release preparation according to claim 1. 10) The incorporation rate of the physiologically active substance into the sustained release preparation manufactured in claim 7 is 80% or more, and the loading rate is 0.1 to 80%.
The sustained release preparation according to claim 1, characterized in that the amount is wt%.