JPH0761959B2 - Silicone elastomer-based sustained release formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to a silicone elastomer-based sustained-release preparation, and more particularly to a silicone elastomer-based sustained-release preparation useful for medical and animal husbandry.

[Prior Art and its Problems] Attempts have been made up to now to use silicone elastomers as carriers for removing drugs. Many of them are based on the characteristic of silicon, that is, they are relatively soluble to fat-soluble and low molecular weight (1000 or less), and estradiol as a drug,
It dealt with nitroglycerin, etc. On the other hand, for water-soluble organic low-molecular or high-molecular compounds, it was said that silicone elastomer is not preferable as a carrier,
Deen Hsieh et al. Described a method of increasing the permeability of a fat-soluble organic low molecular weight compound, that is, a method of adding a water-soluble admixture (for example, polyethylene glycol 400) or an oil plasticizer (for example, polydimethylsiloxane liquid). We have reported the application of sustained release of biopolymers such as bovine serum albumin (BSA) and chymotrypsin from silicone elastomers [Pharmaceutical technology 39-49].
Page (1985)], the drug was contained at a high content of 20 to 50% by weight with respect to the silicone elastomer, and good release was not observed at 20%, for example.
It may be possible to use such a high content for easily available proteins such as BSA and chymotrypsin, but it is actually possible to use such a high content for proteins such as interferon and growth hormone that are active in very small amounts. It is not possible to do so, and even if it is considered to be active even in a small amount, it is not realistic to contain a large amount. Further, even if a proper amount for treatment is contained, the release rate of the silicone elastomer from the matrix is theoretically proportional to the square root of the initial content of the drug, so that there is a drawback that a preferable amount cannot be obtained with a small amount. ing. Furthermore, since many of these proteins that are active in trace amounts are relatively unstable, it is necessary to maintain stability during long-term use as a sustained-release preparation. is there. The above-mentioned problems have not been solved in the conventional silicone elastomer matrix and the system in which the above-mentioned co-mixing agent is added. In fact, it is suggested that in the case of chymotrypsin release, the activity of chymotrypsin is reduced within the silicone elastomer matrix.

[Means for Solving the Problems] As a result of intensive investigations by the present inventors to solve the above problems, when the drug was blended with a silicon elastomer together with albumin, the drug was stabilized and was excellent. We have found the fact that such a release is achieved.

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

DETAILED DESCRIPTION OF THE INVENTION The drug used in the present invention may be either a high molecular weight substance other than albumin or a low molecular weight substance, but the technical feature of the present invention is that the high molecular weight drug has a molecular weight of about 1,000 to about 500,000. Better demonstrated in. Such high molecular weight drugs include peptides, proteins, glycoproteins, polysaccharides, etc.,
In particular, a high molecular weight drug which has a small amount of activity and is desirably administered continuously for a long time, for example, a drug having a growth promoting action, a bone metabolism related action, a blood column lysis action, an immunomodulating action and the like is preferably used. Further specific examples are shown below.

Examples of the drug having a growth promoting action include growth hormone (GH), growth hormone releasing factor (GRF) or somatomedin (SM). GRF is a peptide showing GH releasing activity, and the activity has been recognized for each of several kinds of peptides each consisting of 44, 40, 37 or 29 amino acids, but any of them may be used in the present invention, and a mixture thereof may also be used. But it's okay. SM is recognized as the somatomedin group, and is SM-A, SM-B, SM-
Examples include C and IGF (insulin-like growth factor) -I and IGF-II, as well as MSA (multiplication stimulating activity). Furthermore, SM-C
Is reported to be the same substance as IGF-I, but any substance may be used in the present invention, or a mixture thereof may be used. Examples of the drug having a bone metabolism-related action include calcitonin. Examples of the drug having a blood column dissolving action include tissue plasminogen activator (TPA). Examples of drugs having an immunomodulatory action include interferon (IFN),
Interleukin (IL), colony stimulating factor (CSF),
Examples include macrophage activating factor (MAF) and macrophage migration inhibitory factor (MIF). The interferon referred to here may be any interferon such as α, β, γ, or a combination thereof. Similarly, interleukins are IL-I, IL-2 or
Any of IL-3 or the like may be used, and the colony stimulating factor is mu
lti-CSF (multifunctional CSF), GM-CSF (granulocyte-monocyte macrophage CSF), G-CSF (granulocyte-CSF) or M-CSF
(Monocyte macrophage CSF) Any other CSF or a mixture thereof may be used. Also for MAF and MIF, each subclass expected to be purified and separated by future research is expected to be a glycoprotein or protein having a similar molecular weight, and sustained release is possible by applying the present invention. it is conceivable that. Further, the peptides, proteins, glycoproteins, etc. used in the present invention may be obtained by any of a substance extracted from a living body, an artificial synthetic substance or a gene recombination method, regardless of the production method.

Low-molecular weight drugs include anti-inflammatory agents (eg indomethacin, flurbiprofen, ketoprofen, ibuprofen, phenylbutazone), antibiotics (eg,
β-lactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, tetracycline antibiotics, pyridonecarboxylic acid antibiotics, fosfomycin), antitumor agents (eg adriamycin, cisplatin, bleomycin, mitomycin, fluorouracil, vinblastine) , Vincristine), amino acids (eg,
Examples thereof include ascorbic acid, N-acetyltryptophan), antifungal agents, prostaglandins, vitamins and steroids.

Silicone elastomer is an elastic body made of silicon polymer such as methylpolysiloxane, dimethylpolysiloxane, and methylvinylpolysiloxane, and is not particularly limited as long as it is physiologically acceptable, but easy to handle. Considering the stability of the drug against heat and the like, a room temperature curable silicone elastomer is preferable. This is a solid rubber obtained by adding a vulcanizing agent (for example, stanna octoate, chloroplatinic acid) to a liquid elastomer base. [In the formula, n is 100 to 5000, and R is methyl, hydroxy or vinyl. ] A dimethylpolysiloxane represented by, for example, Dow Corning 360, Silastic 382, Dow Corning (Dow Corning)
Corning) MDX-4-4210, etc., formula: [In formula, n is 100-10,000 and m is 1-100. ] A methyl vinyl polysiloxane represented by the following formula, for example, a silicone polymer such as Silastic Medical Grade ETR manufactured by Dow Corning is preferably used.

As albumin, ovalbumin, milk albumin, serum albumin, etc. can be used. Serum albumin is preferable from the viewpoint of drug stabilizing effect and gradual effect, and for example, human serum albumin, bovine serum albumin and the like may be used. Preferably, human serum albumin is used when the preparation of the present invention is applied to humans, and bovine serum albumin is used when applied to cattle.

The silicone elastomer sustained-release preparation of the present invention may be produced by mixing the drug, albumin and silicone elastomer in any order of addition, but is preferably prepared so that a mixture of the drug and albumin can be obtained in a solid state. .

For example, (a) powder drug and powdered serum albumin are mixed in an appropriate ratio, or (b) drug-containing aqueous solution and serum albumin solution are mixed in an appropriate ratio and then lyophilized to obtain a mixed powder, or ( C) A powdered drug is suspended in an appropriate amount of serum albumin aqueous solution and then freeze-dried to obtain a mixed powder.

The obtained mixed powder is mixed with a plasticizer such as dimethyl polysiloxane, if desired, such as Silastic.
) Mix evenly with liquid elastomer base with 360 added. Then, a curing agent such as stanna octoate is added and mixed thoroughly. This mixture can be molded by filling it in an arbitrary mold and allowing it to stand at room temperature for curing. It is also possible to mold into a structure in which a drug-free inert core is coated with a silicon elastomer containing a drug and albumin. As the inert core, a material having low toxicity may be used, but an elastic polymer is preferable, and a siligone elastomer is particularly suitable from the viewpoint of handling. The formulations of the present invention include pharmaceutically acceptable stabilizers, preservatives, soothing agents, solubilizers, and additives for controlling moldability and drug release, such as water-soluble admixtures (eg, polyethylene). Glycol 400, polyethylene glycol 200, ethylene glycol, glycerol, polysorbate 80, sodium alginate, L-
Alanine, sodium chloride), a fat-soluble admixture (for example, dimethylpolysiloxane) and the like can be added if necessary.

Alternatively, a hollow container is cast-molded with a silicone elastomer or a mixture of the elastomer and albumin, and the drug or the mixture of the drug and albumin is contained in the container, and permeation and membrane permeation for controlling the release property from the container. It is also possible to prepare a sustained-release preparation of the type. The drug or a mixture of the drug and albumin may be in a solid form, a liquid form, a gel form or the like, and if necessary, various pharmaceutically acceptable additives or substances for controlling drug release properties as described above may be used. Can be added.

The shape of the preparation thus obtained is spherical, hemispherical,
It can be cylindrical, needle-shaped, tube-shaped, button-shaped, sheet-shaped, capsule-shaped, microcapsule-shaped, etc., molded into a shape suitable for the site to be used, and administered by a method such as implantation in a living body or insertion into a body cavity. can do. Particularly useful shape is 4m
m or less, preferably about 0.5-2 mm diameter and 50 mm or less,
It is preferably cylindrical, needle-shaped, or tube-shaped having a length of about 5 to 30 mm. According to this shape, it is possible to easily administer it in a living body using a syringe or the like without performing surgery. is there. Examples of the administration device include a fiberscope, a forceps needle, an indwelling needle, and the administration device described in JP-A-60-227772. More preferably, if the diameter is molded to 1.7 mm or less, administration can be more easily performed using a normal indwelling needle (14G). The formulation of the present invention is applicable to humans, cattle,
It can also be applied to mammals such as sheep, pigs, rabbits and chickens.

The content of the drug contained in the sustained-release preparation of the present invention can be widely varied depending on the dose of the drug, the duration of the drug, the release rate, etc., but usually 50% by weight or less from the viewpoint of moldability. , Preferably 1 to 20% by weight. Generally, albumin is 50% by weight or less, preferably 20 to 30% by weight,
Silicone elastomer is 50% by weight or more, preferably 70
~ 90 wt%, plasticizer 45 wt% or less, preferably 1 ~
20% by weight, curing agent 15% by weight or less, preferably 1-10
Used in wt%. In addition to the drug content and albumin content, the release rate of the drug can be adjusted by adding a plasticizer or a cosolvent (eg, glycerin or polyethylene glycol).

[Effect of the Invention] The silicoelastomer sustained-release preparation of the present invention is characterized in that it contains albumin together with the drug, which achieves stabilization of the drug (particularly high-molecular-weight drug) and improvement of sustained-release. It was

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

Example 1 Sustained Release Formulation (I) Silastic 382 0.75 g and Dow Corning 360
0.75 g was kneaded and human serum albumin (HSA) 64
2 mg was added and kneaded. Stanna Octet 110
After adding mg and further thoroughly kneading, the mixture was poured into a polypropylene tube having an inner diameter of 2.9 mm and left at room temperature for 24 hours for curing. Remove the silicone elastomer from the tube,
It was cut into a length of 25 mm to obtain a columnar matrix type preparation.

Sustained Release Formulation (II) Silastic 382 1.35g, Dow Corning 360
Using 0.15 g, HSA 642 mg, and stanna octate 110 mg, the same procedure as in the preparation of the sustained-release preparation (I) was carried out to obtain a cylindrical matrix preparation having a diameter of 2.9 mm and a length of 25 mm.

Sustained-release preparation (III) Using Silastic 382 1.5 g, HSA 642 mg and stanna octate 110 mg, and operating in the same manner as in the preparation of sustained-release preparation (I), columnar shape with a diameter of 2.9 mm and a length of 25 mm To obtain a matrix type preparation.

Example 2 Sustained Release Formulation (IV) (HSA-free Control) Silastic 382 0.5 g and Dow Corning 360 0.
Knead 05 g, add 5 mg of sodium N-acetyltryptophan to this and knead. Stannanas Octate 55 m
Add g and knead further. This was poured into a polypropylene tube having an inner diameter of 4.8 mm and left at room temperature for 24 hours to cure. The silicone elastomer was removed from the silicone tube and cut into a length of 10 mm to obtain a columnar matrix type preparation.

Sustained release formulation (V) (formulation of the invention) 0.5 g of Silastic 382 and Dow Corning 360 0.
05 g was kneaded, and 5 mg of N-acetyltryptophan sodium was dissolved in 0.93 ml of 25% HSA solution and freeze-dried was added thereto, and kneaded. Add 55 mg of stanna octate and knead thoroughly. Inject this into a polypropylene tube with an inner diameter of 4.8 mm, leave it at room temperature for 24 hours,
Cured. The silicone elastomer was removed from the tube and cut into a length of 10 mm to obtain a columnar matrix type preparation.

Example 3 Sustained Release Formulation (VI) (Sodium Chloride Containing, HSA Not Containing Control) Silastic 382 7.0 g and Dow Corning 360 0.
7 g was kneaded to prepare a silicon base.

To 0.6 g of the above silicon base, 108 mg of indomethacin and 192 mg of sodium chloride are added and kneaded. After adding 60 mg of stanna octate and thoroughly kneading, the mixture was poured into a polypropylene tube having an inner diameter of 2.9 mm and left at room temperature for 24 hours to cure. The silicone elastomer was removed from the tube and cut into a length of 13 mm so that the indomethacin content was 30 mg to obtain a columnar matrix-type preparation.

Sustained release formulation (VII) (formulation of the present invention) Indomethacin 100 mg 25% H to 0.6 g of the above silicon base
Suspend in 0.8 ml of SA solution, freeze-dry, and knead. Add 60 mg of stanna octoate and knead thoroughly. This is poured into a polypropylene tube having an inner diameter of 2.9 mm and left at room temperature for 24 hours to cure. The silicone elastomer was removed from the tube and cut into a length of 12.5 mm so that the indomethacin content was 30 mg to obtain a columnar matrix-type preparation.

Sustained-release preparation (VIII) (HSA-free control) Add 112 mg of indomethacin to 0.6 g of the above silicon base and knead. Add 60 mg of stanna octate and knead thoroughly. The mixture is poured into a polypropylene tube with an inner diameter of 2.9 mm and left at room temperature for 24 hours to cure. Remove the silicone elastomer from the tube,
A columnar matrix-type preparation was obtained by cutting into a length of 10 mm so that the indomethacin content was 30 mg.

Example 4 Sustained Release Formulation (IX) (Formulation of the Invention) Silastic 382 1 g and Dow Corning 360 0.1 g
Knead. To this, 2.2 ml of 2.6 × 10 ⁶ IU / ml α-interferon and 2.2 ml of 25% HSA solution are mixed, and the lyophilized product is added and kneaded. Add 166 mg of stanna octate and knead thoroughly. Inject this into a polypropylene tube with an inner diameter of 4.8 mm, leave it at room temperature for 24 hours,
Let it harden. The silicone elastomer was removed from the tube and cut into a length of 12 mm to obtain a matrix type preparation.

An example of the in vitro release test of the obtained sustained-release preparation is shown below.

Test Example 1 Comparison of HSA Release Behavior by Changing Silicone Elastomer Composition Each of the sustained release preparations (I), (II) and (III) prepared in Example 1 was placed in 20 ml of physiological saline and shaken at 25 ° C. H (amplitude 4 cm, 60 reciprocations / min) and H released from the preparation
SA was quantified by measuring the absorbance at 280 nm to determine the cumulative release amount. The results are shown in Fig. 1. In the figure, I, II and III
Figure 3 is the release curves obtained with formulations (I), (II) and (III) respectively.

As is clear from FIG. 1, when the composition of the silicone elastomer is changed, the release behavior of HSA is different. Zero-order release was observed in the sustained-release preparation (II).

Test Example 2 Release-enhancing effect of N-acetyltryptophan sodium by addition of HSA The sustained-release preparations (IV) and (V) produced in Example 2 were subjected to a release test in the same manner as in Test Example 1. The sustained release formulation (IV) of N-acetyltryptophan sodium was quantified by absorbance measurement, and the sustained release formulation (V) was quantified by high performance liquid chromatography (HPLC) to determine the cumulative release amount. Results are shown in FIG. IV and V in the figure
(However, V-b is the value for HSA, V-a is the value for N-acetyltryptophan sodium)
3 is a release curve obtained with the A-free control formulation (IV) and the HSA-containing formulation of the present invention (V).

As is clear from FIG. 2, the preparation of the present invention (Va)
Compared to the HSA-free control formulation (IV), the addition of HSA increased the release rate of sodium N-acetyltryptophan by about 10-fold. Therefore, it was revealed that HSA exhibits a drug release promoting effect.

Test Example 3 Indomethacin release accelerating effect by addition of HSA The sustained-release preparations (VI), (VII) and (VIII) produced in Example 3 were each placed in 10 ml of physiological saline and shaken at 25 ° C to release the preparation. Cumulative release of indomethacin was determined by HSAC. Results are shown in FIG. VI, VII and VIII in the figure are release curves obtained by the HSA-free and sodium chloride-containing control formulation (VI), the HSA-containing formulation (VII) and the HSA-free control formulation (VIII) of the present invention, respectively.

HSA was also found to be effective for the release of indomethacin. Also, the formulation (VI) containing sodium chloride, which is a water-soluble admixture, released less than the control (VIII).

Test Example 4 Releasability of α-interferon The sustained release preparation (IX) of the present invention produced in Example 4 was treated with 0.5% H.
The mixture was placed in 20 ml of PBS buffer containing SA and shaken at 25 ° C., and α-interferon released from the preparation was quantified by a radioimmunoassay method to determine a cumulative release amount. The fourth result
Shown in the figure. In the figure, IX is the release curve obtained by the formulation (IX).

α-Interferon is an unstable and minute amount of active protein, but stabilization was achieved by mixing with HSA, and a therapeutic release amount was obtained.

It is clear from the following basic experimental results that interferon is an unstable substance by nature and is stabilized by the presence of albumin. That is, when the various solutions of interferon were kept at 37 ° C. for 1 week and the activity yield (%) of interferon was measured, the following results were obtained.

Solution Interferon activity yield (%) PBS buffer 3.0% Tris / Gly buffer 3.9% 0.5% HSA / PBS buffer 88.4% FIG. 4 showing the results of Test Example 4 is a relatively short period of 10 days after the start of the experiment. It is understood that interferon is released at a considerable active concentration even after 10 days, and that interferon is stabilized, since it gives only the result of the above. However, it is confirmed by a separate experiment that a stable release actually continues for a longer period (for example, 150 days), and a sufficient amount of release is finally achieved.

[Brief description of drawings]

Fig. 1 is a graph showing the release behavior of HSA due to changes in the composition of silicone elastomer, Fig. 2 is a graph showing the effect of HSA addition on the release of sodium N-acetyltryptophan, and Fig. 3 is a water-soluble mixture for the release of indomethacin. FIG. 4 is a graph showing the effect of addition of (sodium chloride) and HSA, and FIG. 4 is a graph showing the release behavior of interferon.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshihiro Takada 1-3-45 Kuragakiuchi, Ibaraki City, Osaka Prefecture Sumitomo Pharmaceuticals Co., Ltd. (56) References JP 59-44310 (JP, A)

Claims (11)

[Claims] 1. A sustained-release preparation containing a drug (excluding albumin), albumin and a silicone elastomer as essential components. 2. The sustained-release preparation according to claim 1, wherein the drug has a molecular weight of 1000 or more. 3. The drug according to claim 1, wherein the drug is selected from peptides, proteins, glycoproteins and polysaccharides.
The sustained-release preparation according to any one of 1 and 2. 4. The drug according to any one of claims 1 to 3, wherein the drug is a high molecular weight substance and has a growth-regulating action, a bone metabolism-related action, a blood column lysis action or an immunoregulatory action. Sustained-release preparation. 5. The sustained-release preparation according to claim 1, wherein the drug is interferon. 6. The sustained-release preparation according to claim 1, wherein the drug is a low molecular weight substance and has an anti-inflammatory effect. 7. The sustained-release preparation according to claim 1, wherein the albumin is serum albumin. 8. The sustained-release preparation according to claim 1, which is a matrix-type preparation using a silicone elastomer as a carrier. 9. The sustained-release preparation according to claim 1, wherein a silicone elastomer film is used as a drug container and the drug is enclosed therein. 10. The sustained-release preparation according to claim 1, wherein the content of the drug is 50% by weight or less. 11. The sustained-release preparation according to claim 1, wherein the content of albumin is 50% by weight or less.