JPH01190627A - Recovery of drug from silicone elastomer drug preparation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application 1] The present invention relates to a method for recovering a drug as an active ingredient from a silicone elastomer preparation.

[Prior art and its problems] Various substances are used as carriers for sustained-release preparations, but they have excellent physical properties such as resistance to tearing, elongation and tensile strength, and biocompatibility. from,
The usefulness of silicone elastomers as biomedical raw materials has attracted attention, and sustained-release preparations using silicone elastomers as carriers have been widely developed. Examples of the silicone elastomer used as a pharmaceutical carrier include Dow Corning ΦMDX-4-4210 medical grade elastomer and Silastida Φ382 medical grade elastomer manufactured by Dow Corning.

By the way, in the manufacturing and distribution process of pharmaceuticals, appropriately maintaining the activity of the drug in the product, that is, quality control, is an essential process in the technical field. For quality control, it is necessary to measure the drug activity in the preparation, and generally, the quality of the preparation is monitored by recovering (extracting) the active ingredient, the drug, from the preparation and measuring its activity. It is taken. Recovery of drugs from pharmaceuticals can sometimes be carried out by immersing the product as is in an appropriate solvent, but usually it is carried out by a suitable combination of crushing, homogenization, ultrasonication, solvent extraction, etc.

Methods for pulverizing pharmaceuticals include applying pressing force and grinding to pulverize, applying impact force with a medium to pulverize, or chopping and pulverizing. However, in the case of pharmaceutical formulations using silicone elastomers as carriers, it is difficult to crush them using normal methods due to the inherent flexibility and flexibility of the elastomers, and the frictional heat generated by the shearing force during the crushing process is difficult to crush. The sample temperature increases,
Heat-labile active ingredients may be decomposed. Such problems are particularly serious when the active ingredient is a physiologically active substance that is unstable to heat. Therefore, there is a need for a method that uses a silicone elastomer as a carrier and can efficiently recover active ingredients from drugs containing thermally unstable active ingredients without decomposing them.

[Means for Solving the Problems] The present inventors have conducted extensive research in order to solve the above problems, and have focused on the fact that the flexibility and visibility of silicone elastomer preparations are lost at low temperatures. The inventors have discovered that pulverization at low temperatures can easily be pulverized without generating frictional heat and prevent the decomposition of the drug, leading to the completion of the present invention.

That is, the present invention provides a method for recovering a drug from a silicone elastomer preparation, which is characterized by pulverizing the preparation under cooling and then extracting the drug with a solvent.

The crusher used in the method of the present invention is not limited to a specific one, but a turbo crusher or a hammer mill Eve crusher is preferred. The material needs to be a metal that does not cause brittle fracture at extremely low temperatures ranging from room temperature to about -200°C.

Although the method of the present invention is useful for recovering drugs from ordinary pharmaceuticals, it is particularly effective for recovering drugs from silicone elastomer preparations containing heat-labile drugs. Such thermolabile substances include, for example, substances selected from the group consisting of prostaglandesins, prostacyclins, vitamins, and physiologically active peptides and proteins. The method of the invention may be applied to formulations containing these substances alone or in mixtures, or mixtures or complexes of these active ingredients with one or more other substances. Good too. In the above, physiologically active peptides or proteins include growth hormone, growth hormone-releasing factor, somatomedin, luteinizing hormone-releasing factor, interferon, interleukin, tumor necrosis factor, colony formation stimulating factor, tissue plasminogen activator, etc. Finger 4”.

In addition to thermal decomposition of active ingredients in drugs, thermal decomposition of additives in preparations such as excipients, stabilizers, preservatives, and soothing agents, or active ingredients caused by their thermal decomposition products, can also occur. Decomposition also affects product quality. Those skilled in the art will readily understand that the method of the present invention solves such problems.

The silicone elastomer used in the preparation to which the method of the present invention is applied is not particularly limited as long as it is physiologically acceptable; and a known crosslinking agent,
Silicone elastomers containing curing catalysts and fillers can be used. Specific examples include Silastic 0382 medical grade elastomer manufactured by Dow Corning, Dow Corning ΦMDX-4-4210 medical grade elastomer, and Silastic ■ Medical Grade ETR elastomer. Crosslinking agent (fil'ing agent) for these silicone elastomers
A carboxylic acid metal salt such as stannous ophtate or a platinum compound such as chloroplatinic acid may be used. The drug to which the method of the present invention can be applied is not limited to a specific dosage form, but it is recommended to use a sample that has been coarsely ground in advance for pulverization. Delicious.

In the method of the present invention, under cooling in the crushing process means that the sample to be crushed is sufficiently cooled as described below, and must be constantly cooled during the crushing. That doesn't mean there aren't any. However, it is preferable to pre-cool the sample and the grinding chamber prior to grinding and grind the sample while continuing to cool.

The sample can be cooled by mixing the sample with an appropriate amount of a coolant such as dry ice, by exposing the sample to dry ice or a low temperature vaporized gas such as liquid nitrogen, or by immersing the sample in a coolant such as liquid nitrogen. The cooling of the refrigerant chamber can also be done using a refrigerant such as dry ice or liquid nitrogen.
Alternatively, it can be carried out using those low-temperature vaporized gases.

The pulverization process can be performed by supplying the sample to a pulverization chamber together with a refrigerant such as dry ice or liquid nitrogen, or by pulverizing the sample while blowing low-temperature vaporized gas of the refrigerant. At this time, the temperature inside the chamber can be appropriately controlled by appropriately controlling the supply amount of the refrigerant according to the characteristics of the sample, the rotation speed of the pulverizer m1, and the like. The temperature of the sample during the pulverization process is usually low enough to suppress the elasticity of the silicone elastomer to a sufficient extent to improve the pulverization condition and to avoid decomposition of the active ingredient and/or additives due to heat generation. , -50
It is preferable to maintain the temperature below ℃, -70℃~-200℃
It is particularly preferred to maintain the temperature at °C. However, if the time required for such a grinding process is judged to be sufficiently short, and if it is ensured that the elasticity of the silicone elastomer is suppressed and that the decomposition of active ingredients and/or additives due to heat generation is avoided, the overall grinding process can be carried out at a higher speed. Needless to say, it can be carried out at a temperature around room temperature, for example.

It is considered that the particle size of the pulverized particles can have a large effect on the recovery rate of the target drug and the time required for recovery. As the particle size of the ground sample decreases, it is expected that the rate of drug release from the silicone formulation will increase due to the increase in the specific surface area of the particles. In practice, considering the technical problems in the collection operation and the time required for collection, the particle size is approximately 1. (ls+a or less, particularly preferably about 0.
Good drug recovery is achieved when In+m or less.

The particle size here can be evaluated using, for example, the Luzex screen analyzer LUZBX-500 manufactured by Nippon Regulator, and indicates the maximum flame unless otherwise specified. , envelope perimeter,
Circle equivalent diameter
etc. may be used.

Next, the obtained pulverized sample is extracted with a suitable solvent and subjected to further steps such as determination of the active ingredient.

Here, when returning the ground sample to the normal atmosphere, if the sample is highly hygroscopic, the following points need to be kept in mind. In other words, if an extremely low-temperature crushed sample is collected as it is in a room-temperature atmosphere, it will easily absorb moisture, so it is desirable to send dry air to the collection site of the crushed sample in advance and return the sample to room temperature at that site before taking it out and collecting it. .

The extraction step is carried out by conventional methods used to extract similar target substances from mixtures.

Such a method can be used if the extract is an aqueous solvent: 1)
The extraction conditions can be optimized by appropriately selecting the H1 salt concentration, ionic strength, buffer components, temperature, etc., and adding albumin, surfactant, and organic solvent, if desired. Furthermore, when the substance to be extracted is a substance that is stable in organic solvents, it may be extracted using an extract liquid containing an organic solvent as a main component.

[Operations and Effects of the Invention] According to the method of the present invention, a silicone elastomer preparation containing a heat-labile physiologically active substance as an active ingredient is decomposed or decomposed while controlling the elasticity and flexibility of the preparation. It can be efficiently recovered without deactivation. Therefore, according to the method of the present invention, it is possible to appropriately control the quality of silicone elastomer preparations, and it is possible to contribute to effective treatment in the field of clinical medicine.

The present invention will be explained in more detail with reference to experimental examples below.

These experimental examples are not intended to limit the invention in any way.

X count 1, preparation of silicone elastomer preparation A solution of α-IFN dissolved in distilled water for injection (potency 2. Ox l O
'(lv/xff)) and 2.5% human serum albumin (
H9A) solution was mixed, thoroughly stirred, and then lyophilized to give an IFN titer of 5.5XlO' (I U/s+g
) was obtained. Silastic ■ (S 1las
tic) 382 2,0 (g) and this mixed powder 0.
After combining 857 (g), Stanus ophtate 0. +
5 (g) was added and allowed to stand at room temperature to harden. After 24 hours, it was removed from the mold to obtain a cylindrical silicone preparation with a diameter of 4.8 mm and a height of IOn+m. This formulation is about 3. O
It contained α-IFN of X l O” (I tJ).

2. Grinding of silicone elastomer preparation The matrix preparation obtained above was used as a pulverization sample. This pulverized sample was immersed in liquid nitrogen, and a pulverizer (MRK-Ret
Liquid nitrogen was continuously injected into the grinding chamber of the Sch ultracentrifugal grinder 18-30) for preliminary cooling before grinding. Next, the sample was supplied to the crushing section together with liquid nitrogen, and the sample was crushed while injecting the liquid nitrogen. After pulverization, dry air at room temperature is sent into the pulverized sample collection section, and when the sample reaches room temperature, it is taken out and the equivalent circle diameter (Heywood
A fine powder with a diameter of about 0.1 mm was obtained.

α-IFN was extracted from the fine powder using PBS buffer (pH 7,4) containing 0.5% tlSA. In the extraction step, the recovery rate was calculated by sampling over time and measuring the amount released per unit time using radioimmunoassay. The results are shown in Figure 1 (-).

Experimental example 2 Same as l in experimental example 1, diameter 4.8 am, length 10+
A silicone elastomer formulation of sm was obtained. This matrix formulation was used as a ground sample.

The crushed sample was cut with a sharp cutter knife to obtain a coarsely crushed sample approximately 2 mm square. Next, this coarsely ground sample was homogenized with a regular (Potter-E1veh3em) type Teflon homogenizer under water cooling, and from the obtained ground sample, a PBS buffer containing 0.5% H9A (pH 7,4
) was used to extract α-IFN. In the extraction process,
The recovery rate was calculated by sampling over time and measuring the amount released within a unit time using radioimmunoassay. The results are shown in Figure 1 (0).

Kangari Koikage 1, Preparation of silicone elastomer preparation A solution of human growth hormone (hGH) dissolved in distilled water for injection (potency 2)
.

Silastic ■ (S 1lastic) 3 B 2
After mixing 200 (mg) of this mixed powder with 50 (o+g) of this mixed powder, 15 (mg) of Stanus ophtate was added and left to stand at room temperature to harden. After 24 hours, remove from the mold,
4.0mmX4. A rectangular parallelepiped silicone preparation of Oa+@X6.0 was obtained. This formulation contained approximately 2.93 (ltJ) of hGH.

2. Grinding of silicone elastomer preparation The matrix preparation obtained above was used as a pulverization sample. This crushed sample was immersed in liquid nitrogen, and on the other hand, a crusher (M n K -Re
Grinding chamber of Tsch ultracentrifugal grinder 18-30) (
Liquid nitrogen was continuously injected into the chamber for preliminary cooling before pulverization. Next, the sample is supplied to the crushing section together with liquid nitrogen,
Grinding was carried out while injecting liquid nitrogen. After grinding,
Dry air at room temperature is sent into the crushed sample collection section, and when the sample reaches room temperature, it is taken out and the equivalent circle diameter (Heywood
A fine powder of approximately 0.1 mm in diameter was obtained. hGH was extracted from the fine powder using a P[3S warm solution (pH 7,4) containing 0.5% ■SA. In the extraction step, the recovery rate was calculated by sampling over time and measuring the amount released per unit time using high performance liquid chromatography. The results are shown in Figure 2.

[Brief explanation of the drawing]

Figures 1 and 2 show α-IFN and h
It is a graph created by measuring the recovery rate of GI-1 from a silicone elastomer preparation over time. Patent applicant: Sumitomo Pharmaceutical Co., Ltd. (and one other person) representative
Person Patent attorney Maeda Ao (and 1 other person) Figure 1 1 binding M 411tM +
2nd M 4th 6th tank 1■

Claims (1)

[Scope of Claims] 1. A method for recovering a drug from a silicone elastomer preparation, which comprises extracting the drug after crushing the preparation while cooling. 2. The method according to claim 1, wherein the cooling temperature is -50 to -200°C. 3. The method according to claim 1 or 2, characterized in that the preparation is pulverized to a particle size of 1.0 mm or less. 4. The method according to any one of claims 1 to 3, wherein the drug in the preparation is a heat-labile substance. 5. The drug in the preparation contains prostaglandins, vitamins,
and one or more substances selected from the group consisting of bioactive peptides and bioactive proteins. 6. The bioactive peptide or protein is selected from the group consisting of growth hormone, growth hormone releasing factor, interferon, interleukin, tumor necrosis factor, colony formation stimulating factor, and tissue plasminogen activator. A method according to claim 5.