JPS62174007A - Slow-releasing preparation containing silicone elastomer - Google Patents

Abstract

PURPOSE:To produce the titled slow-releasing drug preparation, by adding a drug such as growth regulator, osteometabolism-relating agent, thromobolytic agent, immunorgulator, anti-inflammatory agent, etc., and albumin to a silicone elastomer and using the elastomer as a matrix or using a membrane of the elastomer as a drug container. CONSTITUTION:A silicone elastomer containing <=50wt% drug and <=50wt% albumin is used as a matrix or a membrane of the elastomer is used as a drug container to obtain the objective slow-releasing drug preparation. The compounding of a silicone elastomer with a drug together with albumin attains the stabilization and slow releasing of the drug. Highest effect can be achieved when the drug is a polymeric drug having a molecular weight of 1,000-500,000 (e.g. peptide, protein, polysaccharide, etc.). The silicone elastomer is preferably a cold-curing elastomer such as dimethylpolysiloxane of formula (n is 100-5,000; R is CH3, OH or vinyl).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a silicone elastomer sustained release preparation, particularly to a silicone elastomer sustained release preparation useful medically and in animal husbandry.

V. Prior Art and its Problems] Attempts have been made to use soric elastomers as carriers for sustained release of drugs.

Many of these are based on the characteristics of Solicon, that is, it is fat-soluble and relatively permeable to low molecular weight substances (i (1000 or less). On the other hand, silicone elastomer is preferred as a carrier for water-soluble organic low molecules and polymer compounds.
It was said that there was no such thing, but Dean H.
reported a method to increase the permeability of fat-soluble organic low molecular weight compounds, that is, a method of adding water-soluble admixtures (e.g., polyethylene glycol 400, sodium chloride) and oil-based plasticizers (e.g., polymethylene glycan solution). have reported the sustained release of biopolymer substances such as BS'A and chymotrypsin from silicone elastomers by applying this method [Pharmaceutical Technology (Pharmaceutical Technology)]
teanology) 39-49N (1985)]
However, both are 20 to 50 for silicone elastomer.
It contains a drug at a high content of up to 20% by weight, and good release is not observed at 20%, for example. B.S.A.

Although it may be possible to use such a high content of readily available proteins such as chymotrypsin, it is practically impossible to contain such high amounts of proteins such as interferon and growth hormone, which are active in very small amounts. However, it is not realistic to contain a large amount, considering that it shows activity in a trace amount. Furthermore, even if an appropriate amount is included for treatment, the rate of release from the silicone elastomer matrix is theoretically proportional to the square root of the initial drug content, so if it is included in a trace amount, a desirable release cannot be obtained. ing. Furthermore, since many of these proteins that are active in trace amounts are relatively unstable, if the purpose is to use them as sustained-release preparations over a long period of time, stability must be maintained during that time. It is necessary. In the conventional Noricon elastomer matrix and the system in which the above-mentioned co-mixing agent is added, the problem mentioned in 1. is not solved. In fact, in the case of chymotrypsin release, it has been suggested that the activity of chymotrypsin is reduced within the elastomer matrix.

Means for Solving Problem U] As a result of intensive investigation to solve the above problem, the present inventors found that by blending a drug with albumin into Noricon elastomer, the drug is stabilized. Shinoko also found out that good release was achieved.

That is, the present invention provides a sustained release preparation characterized in that a drug (excluding albumin) and albumin are contained in a Noricon elastomer. In silicone elastomer-based sustained release preparations containing albumin, the active ingredient drug is stabilized, regardless of whether it is fat-soluble or water-soluble, and regardless of whether it has a high molecular weight or a low molecular weight. and achieve good release.

[The drug used in the detailed description of the invention may be either a high molecular weight substance or a low molecular weight substance other than albumin, but the technical features of the present invention are Shows off well. Such high molecular weight drugs include peptides, proteins, glycoproteins, polysaccharides, etc. High molecular weight drugs are particularly active in small amounts and are desirable to be administered continuously over a long period of time, such as growth promoting effects, bone metabolism related effects, etc. Drugs having thrombolytic effects, immunomodulatory effects, etc. are preferably used. Further specific examples are shown below.

Examples of drugs that have a growth-promoting effect include growth hormone (GI-1) and growth hormone-releasing factor (GRF).
or somatomedin (SM).

GRF is a peptide that exhibits CI-T release activity, and activity has been recognized for several types of peptides each consisting of 4.4, 40.37 or 29 amino acids.
When used in the present invention, any of them may be used, or a mixture thereof may be used. SM is recognized as a somatomedin group, and includes SM-A, SM-B, and SM-C.
and I GF (insulin-like growth factor)-I and rGF
In addition to -11, examples include MSΔ (multiplication stimulating activity). Furthermore, although there are reports that it is the same substance as S'M-C GF-1, any substance may be used in the present invention, or a mixture thereof may be used. Examples of drugs having bone metabolism-related effects include calcitonin. Examples of drugs having thrombolytic effects include tissue plasminogen activator (TPA).

Examples of drugs with immunomodulatory effects include interferon (IFN), interleukin (IL), colony stimulating factor (C8F), and macrophage activating factor (
MAR) and macrophage fugue inhibition factor (Mr). The interferon mentioned here is α,
Any interferon such as β, γ, etc. may be used, or a combination thereof may be used. Similarly, the interleugin may be IL-I, IL-2 or TL-3, and the colony stimulating factor may be multi-CS.
F (pluripotent C5F), GM-C8F (granulocyte-monocyte-macrophage C8F'), G-CS P (granulocyte-
C6F) or M-C8F (monocyte-macrophage C9F)
) Any other C8F may be used, or a mixture thereof may be used. As for MAP and MIF, each Zab class that is expected to be purified and isolated through future research is expected to be a glycoprotein or protein with similar molecular residues, and it is possible to achieve sustained release of both by applying the present invention. It is believed that there is. In addition, the peptides, proteins used in the present invention,
Glycoproteins and the like may be obtained by extracts from living organisms, artificially synthesized substances, or genetically recombinant methods, regardless of the manufacturing method.

Low molecular weight drugs include anti-inflammatory agents (e.g. indomethacin, flurbiprofen, ketoprofen, ibuprofen, phenylbutacin), antibiotics (e.g.
β-lactam antibiotics, aminoglycon antibiotics, macrolide antibiotics, tetrazycline antibiotics, pyridonecarboxylic acid antibiotics, fosfomycin), antitumor agents (e.g. adriamycin, spradine, pleomycin, mitomynon, fluorouraful, vinblastine, pink lysine), amino acids (e.g.
Examples include ascorbic acid, N-acetyltryptophan), antifungals, prostaglandins, vitamins, and steroids.

Noricon elastomer is made of medylborinoloxane, nomedylborinologizan, nomethylmethylborinologizan,
It is an elastic body made of a silicone polymer such as, and there are no particular restrictions as long as it is physiologically acceptable. , room temperature curing type Noricon elastomer is preferred.

This is a solid rubber obtained by adding a vulcanizing agent (for example, stannous ophtate, chloroplatinic acid) to a liquid elastomer base. Methyl, hydroxo or vinyl. ] Dimethylborisiloxane represented by, for example, Dow Corn-in (manufactured by Dow Corning Company)
g fossa) 360, Silastic (S 1lastic fossa) 382, Dow Corning (Dow Corning fossa) MDX-4-4210, etc., where n is 100 to +0000 and m is 1 to 100. ] Methylvinylbolysilogysan represented by, for example, Silastic (S 1las-ti
c) Silicone polymers such as Medical Group ETR are preferably used.

As albumin, ovalbumin, milk albumin, serum albumin, etc. can be used.

From the viewpoint of drug stabilization effect and sustained release effect, serum albumin is preferred, and for example, human serum albumin, bovine serum albumin, etc. may be used. Preferably, human serum albumin is used when the formulation of the invention is applied to humans, and bovine serum albumin is used when applied to cattle.

The Noricon elastomer sustained release preparation of the present invention may be manufactured by mixing the drug, albumin, and Noricon elastomer in any order of addition, but it is preferable to mix the drug and albumin in a solid state. Prepare.

For example, (a) a powdered drug and a powdered T111 albumin are mixed in an appropriate ratio, or (b) a drug-containing aqueous solution and a serum albumin aqueous solution are mixed in an appropriate ratio and then lyophilized to obtain a mixed powder. Or (c) suspend an appropriate amount of the powdered drug in an aqueous serum albumin solution, and then freeze-dry to obtain a mixed powder.

The obtained mixed powder is optionally mixed with a plasticizer consisting of dimethylpolyroxane, such as Silastic (S 1l).
Mix uniformly with the liquid elastomer base to which 360% of the liquid elastomer base is added. A curing agent, such as stannous ophtate, is then added and mixed thoroughly. This mixture can be molded by filling it into any mold and leaving it at room temperature to harden. Alternatively, it can be molded into a structure in which an inert core not containing a drug is coated with a silicone elastomer containing a drug and albumin. The inert core may be any feed material with low toxicity, but elastic polymers are preferred, and silicone elastomers are particularly suitable from the viewpoint of handling. The formulation of the present invention contains pharmaceutically acceptable stabilizers, preservatives, soothing agents, solubilizing agents, and other additives that adjust moldability and drug release properties, such as water-soluble admixtures (e.g., Polyethylene glycol 400, polyethylene glycol 200, ethylene glycol, glycerol, polysolhe-1.80, sodium alginate, I7-alanine, sodium chloride),
A fat-soluble admixture (for example, polydimethylsiloxane) or the like can be added as necessary.

Alternatively, a hollow container is cast-molded with Noricon elastomer or a mixture of the elastomer and albumin, and a membrane containing the drug or the mixture of the drug and albumin therefrom controls permeation and release. It is also possible to prepare a permeable sustained release preparation. The drug or the mixture of the drug and albumin may be in any form such as solid, liquid, or gel, and may be added with various pharmaceutically acceptable additives or substances for adjusting drug release properties as described above. You can add.

The shapes of the preparations obtained in this way are spherical, hemispherical,
It can be in any shape such as cylinder, needle, dupe, button, sheet, capsule, or microcapsule, and is molded into a shape that suits the site of use and administered by implantation in a living body, insertion into a body cavity, etc. can do. Particularly useful shapes are 4
cylindrical, needle-like, tube-like with a diameter of 0.5 mm or less, preferably about 0.5 to 211π and a length of 50 mm or less, preferably about 5 to 30 yttm; It can be easily administered into the body using a syringe or the like. Such administration devices include fiberscopes, forceps needles, indwelling needles, and Japanese Patent Application Laid-Open No. 80-227.
Examples include the administration device described in No. 772. More preferably, if the diameter is 1.7 rtrm or less, it can be more easily administered using an ordinary indwelling needle (14G). In addition to being applicable to humans, the formulation of the present invention can be applied to cattle, sheep, pigs,
It can also be applied to mammals such as rabbits and chickens.

The content of the drug contained in the sustained release preparation of the present invention can be varied widely depending on the dosage, duration, release rate, etc., but from the viewpoint of moldability, it is usually 50%
The amount is not more than 1% by weight, preferably 1 to 20% by weight. Generally albumin is 50% by weight or less, preferably 20 to 3% by weight.
0% by weight, silicone elastomer 50% by weight or more, preferably 70-90% by weight, plasticizer 45% by weight or less, preferably 1-20% by weight, curing agent 15% by weight or less, preferably 1 Used at ~10% by weight.

Furthermore, the drug release rate can be adjusted by adding a plasticizer or a co-solvent (eg, glycerin, polyethylene glycol), as well as the drug content and albumin content.

[Effects of the Invention] The silicoelastomer-based sustained release preparation of the present invention is characterized in that it contains albumin together with the drug, thereby achieving stabilization of drugs (especially high molecular weight drugs) and improvement in sustained release. Ta.

[Examples and Test Examples] Next, the present invention will be described in more detail with reference to Examples and Test Examples.

Example 1 Sustained Release Preparation (I) 0.759 g of Silastic Fossa 382 and 0.75 g of Dow Corning Fossa 360 were kneaded, and 642 mg of human serum albumin (1-ISA) was added thereto and kneaded. Stannous ophtate 110yH was added to this, and after thorough kneading, the inner diameter was 2.9 ytrll! The mixture was poured into a polypropylene tube and left at room temperature for 24 hours to harden. Remove the silicone elastomer from the duplex,
It was cut into a length of 25 mm to obtain a cylindrical matrix-type preparation.

Extended release formulation (IJ) Silastic fossa 382 1.35g, Dow Corning fossa 360 0.15! ? , H8A64.2t9 and stannous oftate 1]Omg.
) to obtain a cylindrical matrix-type preparation with a diameter of 2°9 mm and a length of 25 u*.

Sustained release formulation (I [I) Silastic fossa 382 1.5 g, H8A642 shoulder 9
Using 110 mg of stannous ophtate and 110 mg of stannous ophtate, the same procedure as in the preparation of sustained-release preparation (1) was carried out.
A cylindrical matrix-type preparation with a length of 25 ypm and a length of 25 y+m was obtained.

Example 2 Sustained release formulation (TV) (I-ISA-free control) Silastic fossa 382 0.5@ and Dow Corning fossa 360
0.05 Lj is kneaded, and 5 Lj of N-acedeltryptophan sodium is added thereto and kneaded. Add stannous ophtate 55yt9 and roughly knead. This was injected into a polypropylene tube with an inner diameter of 4.8H and left at room temperature for 24 hours. I changed it to E. The silicone elastomer was removed from the silicone dupe and cut into a length of lOmt to obtain a cylindrical matrix-type preparation.

Sustained release formulation (■) (formulation of the present invention) Silastic Fossa 382 0.59 and Dow Corning 3
60 0.05g was kneaded, and to this was added 25% I]SA solution 0.9
Add the lyophilized solution dissolved in 3z4 and knead. Add stannous ophtate 55R9 and mix thoroughly. This was poured into a polypropylene dipole having an inner diameter of 4, 8 mm, and left at room temperature for 24 hours to harden. Remove the silicone elastomer from the duplex,]
It was cut into a length of Oxm to obtain a cylindrical matrix-type preparation.

Example 3 Sustained release preparation (■) (containing sodium chloride, control not containing HSA) Silastic Fossa 382 7.09 and Dow Corning Fossa 360 0.79 were kneaded to prepare a silicone base.

Indomethacin 11 to the above silicon base 0.6LiI
Add 08ytr and 192iy of sodium chloride and knead. After adding 60 m9 of stannous ophtate and thoroughly kneading, the mixture was poured into a polypropylene tube with an inner diameter of 2.9 mm and left at room temperature for 24 hours to harden.

The Noricon elastomer was removed from the duplex and cut into a length of 13zz so that the indomethacin content was 30 m9 to obtain a cylindrical matrix-type preparation.

Sustained-release preparation (■) (Preparation of the present invention) To 0.6 g of the above silicone base, a suspension of 100% solution of indomethacin in 0.8 mQ of 25&H3A solution and freeze-drying is added and kneaded. Stannasoftate 6'
Add Omg and mix thoroughly. This is the inner diameter 2
, 9 m7I into a polypropylene tube and left at room temperature for 24 hours to harden.

The silicone elastomer was removed from the tube and cut into a length of 12.5 inches so that the indomethacin content was 30 Fg to obtain a cylindrical matrix type preparation.

Sustained release preparation (■XH3A-free control) Indomethacin 112m in 0.6g of the above silicone base
Add g and knead. 60mg of stannous ophtate
Add and mix thoroughly. This mixture was mixed with an inner diameter of 2.
Pour into a 9-inch polypropylene tube and leave at room temperature for 24 hours to harden. The silicone elastomer was removed from the dupe and cut into a length of 10 mm so that the indomethacin content was 30 rtrg to obtain a cylindrical matrix type preparation.

Example 4 Sustained release formulation (IXX formulation of the invention) Norastic Fossa 382 1g and Dow Corning Fossa 36
0 Knead 0.1g. This includes 26×106I U/
m(lα~interferon 2.2Rρ and 25% tI
Mix 2 mQ of SA solution, add the freeze-dried solution, and knead. Stannasoftate 16671
g and knead thoroughly. This inner diameter is 4.8
Pour into a polypropylene tube and leave at room temperature for 24 hours to harden. The silicone elastomer was removed from the tube and cut to a length of 12 mm to obtain a matrix-type preparation.

In vitro analysis of the obtained sustained release formulation
An example of a release test is shown below.

Test Example 1 Comparison of release behavior of ISA due to changes in silicone elastomer composition Sustained release formulations (1), (H) and (
1) in 20 mQ of physiological saline and heated at 25°C.
The I-ISA released from the preparation was determined by absorbance measurement at 280 nm, and the cumulative amount released was determined. The results are shown in Figure 1. In the figure, I, ■, and Iff represent the formulation (1), (
Release curves obtained by n) and (Tlt).

As is clear from FIG. 1, the release behavior of I-ISA differs depending on the composition of the silicone elastomer. Zero-order release was observed in the sustained release formulation (Ding).

Test Example 2 Release promotion effect of N-acedeltryptophan sodium due to addition of T-I SAA A release test was conducted in the same manner as in Test Example 1 for the sustained release formulations (JV) and (V) manufactured in Example 2. . N-
Extended release formulation of sodium acetyltryptophan (■)
The constant voltage was determined by absorbance measurement, and the sustained release formulation (V) was quantified by high performance liquid chromatography (T-I PLC) to determine the cumulative release amount. The results are shown in Figure 2. In the figure, IV and ■ (where ■-b is the value for H, SA, and V-a is the value for N-acetyltryptophan sodium) are the values for the ISA-free control preparation (1
2) and the release curves obtained with the HS A-containing formulation (V) of the present invention.

As is clear from FIG. 2, when the formulation (V-a) of the present invention is compared with the control product (■) containing no HS A, HS
Addition of A increased the release rate of sodium N-acetyltryptophan by about 10 times. Therefore, I-I S
It was found that A had a drug release promoting effect.

Test Example 3 Effect of promoting indomethacin release by adding ISA Sustained release preparations (VI), (■) and (■
) each with 10 m0 of physiological saline. Shake at 250C to release indomethacin from the preparation.
The cumulative amount released was determined by LC analysis.

The results are shown in Figure 3. ■, ■, and ■ in the figure are respectively I
Figure 2 is a release curve obtained with a control formulation without SA and containing sodium chloride (■), a formulation containing HS A of the present invention (■), and a control formulation without H8A (■).

I-ISA was also found to be effective for the release of indomethacin. In addition, the formulation (VT) containing sodium chloride, which is a water-soluble mixture, released a smaller amount than the control (■).

Cheng Mujiang ↓ Sustained release behavior of α-interferon The sustained release preparation (IX) of the present invention prepared in Example 4 was mixed with 0.
PBS buffer containing 5% HS A 20*12
After shaking at 5°C, the α-interferon released from the preparation was quantified by radioimmunoassay to determine the cumulative release (■). The results are shown in Figure 4. In the figure, IX is the release curve obtained for formulation (IX).

α-interferon (J is an unstable protein that exhibits activity in trace amounts; however, by mixing ISA, stabilization was achieved and a sufficient amount was obtained for treatment).

[Brief explanation of drawings]

Figure 1 shows the effect of changes in tree 1 elastomer composition.
A graph showing the release behavior of SA.
Figure 3 is a graph showing the effect of the addition of A, Figure 3 is a graph showing the effect of the addition of water-soluble admixture (thorium chloride) and HSA on the release of indomethacin, and Figure 4 is the release behavior of interferon. It is a graph.

Claims (1)

[Scope of Claims] 1. A sustained release preparation characterized in that a drug (excluding albumin) and albumin are contained in a silicone elastomer. 2. The sustained release preparation according to claim 1, wherein the drug is a high molecular weight substance and has a growth regulating effect, a bone metabolism related effect, a thrombolytic effect or an immunomodulating effect. 3. The sustained release preparation according to claim 1, wherein the drug is a low molecular weight substance and has an anti-inflammatory effect. 4. The sustained-release preparation according to claim 1, which has a silicone elastomer as a matrix and releases the drug contained therein continuously for a long period of time. 5. The sustained-release preparation according to claim 1, in which a silicone elastomer membrane is used as a drug container, and the drug encapsulated inside is permeated and released continuously over a long period of time. 6. The sustained release preparation according to claim 1, wherein the drug content is 50% by weight or less. 7. The sustained release preparation according to claim 1, wherein the albumin content is 50% by weight or less.