CA1300016C

CA1300016C - Sustained pulsewise release pharmaceutical preparation

Info

Publication number: CA1300016C
Application number: CA000526271A
Authority: CA
Inventors: Keiji Fujioka; Shigeji Sato; Yoshihiro Takada; Yoshio Sasaki; Nobuhiko Tamura
Original assignee: Sumitomo Pharmaceuticals Co Ltd
Current assignee: Sumitomo Pharmaceuticals Co Ltd
Priority date: 1985-12-28
Filing date: 1986-12-24
Publication date: 1992-05-05
Anticipated expiration: 2009-05-05
Also published as: US5011692A; EP0230654A3; JPH0778017B2; JPS63239212A; EP0230654B1; DE3684446D1; EP0230654A2

Abstract

ABSTRACT
The invention relates to sustained pulsewise release pharmaceutical preparation which comprises drug-containing polymeric material layers (layers A) and polymeric material layers containing the drug in question only in a slight amount or free of the drug (layers B) disposed alternatingly, with the whole surface extending in the direction perpendicular to the layer plane being coated with a polymeric material which is insoluble in water or scarcely soluble in water (polymeric material C). This pharmaceutical preparation of this invention is designed so that active ingredients which should desirably be released pulsewise can be released therefrom in a pulse-like and clinically significant manner and thereby the pharmacological effects of said active ingredients can be maintained for a prolonged period of time.

Description

~L3~)00~i SUSTA~NrD l'ULSEWIS~ RELE~SE PHARM~EUTIC~L PREPARATION
i BACKGROUND OF TIIE lN~ENTION
This invention relates to sustained release pharma-celltical preparations capable of releasing active ingredients sustainedly and in a pulse-like manner. ~ore particularly, the invention relates to sustained release pharmaceutical preparations designed so that active ingredients which should desirably be released pulsewise, such as biologically active trace substances ~e.g. peptide protein type active substances (e,g, hormones, cytokines~, postaglandins, steroids, vitamins and the like) , other active trace substances, anticancer agents and a~tibiotics, can be released therefrom in a pulse-like and clinically significant manner and thereby the pharmacological effects ~, 56~C~
of sa-id active ingredients can be maintained for a pro-longed period of time.
Hithertofore various dosage forms and systems have been designed in an attempt to attain susta;ned release of drugs in a manner such that the drue concentrations can be maintained at clinical therapeutic levels, They bring sustained release to manY kinds of drugs. However, as far as biologically active trace substances such as peptide- protein type active substances (e.g. hormones, cytokines), prostaglandins, steroids, vitamins and the ~L

~3~ L6 like are concerned, the conventional modes of administra-tion which allow continuous drug release are not always 5~ch appropriate, since, in living organisms, ~H~ substances are to be released in a pulsating or pulse-like manner and living organisms have a function to suppress effect of such substance in case of giving them from inside or outside over the physiological level.
For exa~ple, it is known that luteinizing hormone (I,H) is secreted in ovarectomized rhesus monkeys at about 60-minute intervals (Endocrinology, 87, 850-853 ~1970)) and that, in rats, physiologically, growth hormone is secreted at intervals of about 3.5 hours (Endocrinology, 98, 562 (1976)~ and it is also known that negative feed-back is involved in the mechanisms of regulation of growth hormone ~hGII) secretion and it is reported that, in rats, administration of Gll causes decreases in pituitary weight and G~l content and an increase in somatostatin quantity in the hypothalamus (Life Sci., 24, 1589 (1979)) .
Therefore, artificial continuous administration of such substances in large quantities is undesirable to living organisms in many cases.
Pulsewise administration of anticancer agents, anti-biotics and the like is also desirable in certain cases.
In particular, in the case of multiple drug therapy, pulsewise administration of several drugs differing in ~ 3~ 6 site of action in an effective order, for instance, can he expected to produce excellent effects in respect of efficacy, tolerance and reduced toxicity. ~rom such viewpoint, pulsewise administration of drugs has been attempted.
Thus, for example, Langer et al. (J. Membrane Sci., 7, 333 (1980)) propose a pharmaceutical preparation for drug release by magnetic stirring, which comprises a drug substance and magnetic beads mixedly incorporated in a polymer (ethylene-vinyl acetate copolymer) matrix. Drug release is ca~lsed by vibrating the magnetic beads in the matrix by means of an external magnet. This preparation is indeed advantageous in that pulsewise drug release can be effected by actuating the external magnet intermittent-ly, but the patient is restricted of his or her liberty ~ e L~ by an external apparatus including-said- magnet, Moreover, continuous release at a certain rate is inevitable for structural reasons even when magnetic vibration is not effected, so that completely pulsewise release cannot be achieved, Accordingly, an attempt has been made to attain liberaton from external elements, decrease in complicated-ness, and more complete pulsewise release. Thus, a sustained release composite preparation having a multi-layer structure as disclosed by Kaetsu et al. (specifica-.

tion of Japanese Patent Unexamined Publication No. 120618/81) can attain pulsewise drug release in an intrinsic and simple manner without using any external apparatus. This preparation comprises alternatingly disposed drug-containing and drug-free layers, for example drug-containing layers and drug-free layers for envelop-ment of each drug-containing layer.
From the viewpoint of precise pulsewise release, however, such technique yet has room for improvement. There is a fear that in case of a spherical, cylindrical or sheet-type preparation, (disclosed in the specification of Japanese Patent Unexamined Publication No. 120618/81) the release pulse becomes vague due to irregular erosion and diffusion.
SUMMARY OF INVENTION
Accordingly, it is an object of the invention to provide a pharmaceutical preparation with which vaguely pulsewise drug release due to irregular erosion and diffusion can be avoided.
The invention thus provides in one aspect, sustained pulsewise-release pharmaceutical preparation for subcutaneous 2~ embedded administration, which comprises a~ drug-containing polymeric material layers (hereinafter referred to as "layers A") and polymeric material layers which are free from or substantially free from the drug contained in the layers A but may contain a different drug (hereinafter referred to as "layers B") disposed alternatingly, and b) a surface extending in a direction perpendicular to the layers and coated in its entirety with a polymeric material which is insoluble or scarcely soluble in water (hereinafter referred to as "polymeric material C") and in f ~l3~10~

body Eluids.
In another aspect the invention provides a sustained puLsewise-release pharmaceutical preparation for subcutaneous embedded administration, which comprises a) drug-containing polymeric material layers (layers A) and polymeric material layers which are free from or substantially free Erom the drug contained in the layers A but may contain a different drug (layers B) disposed alternatingly, and b) the whole surface extending in a direction perpendicular to the layer plane and one surface in a direction parallel to the layer plane are coated with a polymeric material which is insoluble or scarcely soluble in water and in body fluids.
BRIEF DESCRIPTIOW OF THE DRAWINGS
In the accompanying drawings, Figure l, Figure 2 and Figure 3 each shows, in section, an embodiment of the pharma-ceutical preparation according to the invention. Figure 4 and Figure 5 each shows the results of testing of a pharmaceutical preparation according to the invention for pulsewise drug reIease pattern DETAILED DESCRIPTION OF TH~ INVENTION
The material to be used in forming layers A in accord-ance with the invention is not limited to any particular species but may be any polymeric material which is degradable in living organisms within a certain appropriate period of time and the drug contained therein is released in living organisms. Examples o~
such material are collagen, gelatin/ polylactic acid, polyglycolic acid, poly~lactide-co-glycolide), silicone polymer and polyvinyl acetate.
The polymeric material for formin~ layers B may like-~3~

wise be any polymeric material capable of being degraded in living organisms within a certain appropriate period of time and includes, among others, those examples mentioned above for layers ~.
The polymeric material of layers A and that of layers B may be either the same or different.
The polymeric material C is not limited to any par-ticular species but may be any polymeric material which is insoluble or scarcely soluble in water and in body fluids and is physiologically acceptable and can continue to serve as a coating for the laminatecl structure composed of layers A and layers B until disintegration of ~~ layers A and layers B in living organisms is complete, Examples of such material are silicone poly-mers and polyvinyl acetate. From the viewpoints of ease in handling, thermal stability of drug substances, etc., silicone polymers are particularly prefable.
Suitable examples of the silicone polymers are methyl-polysiloxane, dimethylpolysiloxane, dimethylmethylvinyl-polysiloxane and trifluoropropylmethylpolysioloxane. In particular, there rnay be mentioned dimethYlpolysiloxane species representable by the formula C H 3 ~ C H -`L f ~3 R - S i - O - - S i - O S i - R
l l l C H 3 C H 3 -- n C H 3 .

wherein n is 100-5,000 and R is methyl, hydroxy or vinyl, such as Dow Corn;ng's Dow Corning~ 360, Silastic~ 382 and Dow Corning~ MDX-4-4210, and methylvinylpolysiloxane species having the formula Cl13 ~ CU3 l r Cl13 -I CH3 HzG=CN-Si-O ~ Si-O ~ Si-O ~ Si-CH=CHz Cl13 CH3 n CII=CHz m CH3 wherein n is 100-lO,OO0 and m is 1-100, such as Dow Corning's Silastic~ Medical Grade ETR. These silicone polymers are used in the elastomer form.
Thus, the starting material silicone polymer (silicone elastomer base) to be used in accordance with the invention generally~ in a fluid or viscous liquid form and, upon addition of a curing agent (e.g.
stannous octoate, chloroplatinic acid), turns into a solid rubber-like elastomer (silicone elastomer) to form a coating portion of the pharmaceutical preparation according to the invention.
The starting material silicone elastomer bases mentioned above by way of example may be used either singly or in combination. Por example, silicone elas-tomers more appropriate in degree of curing can be formed by adding Dow Corning~ ~60 in an apPrOPriate amount (e.g.
0-20%, preferably 5-15%, more preferably about 10%) to Silastic~ 382.

.. . .

~3~ L6 The drug to be incorporated in the pharmaceutical preparation according to the invention is not limited to any partlcular species but may be any drug intended for pulsewise release and thus includes, among others, the following.
(1) Biologically active trace substances exemplified by peptide protein type active substances such as hormones [e g.
growth hormone (GH), growth hormone releasing factor (GRF), luteinizing hormone (LH), luteinizing hormone releasing hormone (LH-RH), insulin, glucagon], cytokines ~e.g. interferons (IFN), interleukins (IL), colony stimulating factors (CSF), tumor necrosis factor (TNF), macrophage activating factor (MAF), macrophage migration inhibitory factor (MIF)] and others [e.g.
platelet-derived growth factor (PDGF), insulin-like growth factors (IGFs), somatostatin (SS), epidermal growth factor (EGF), angiotensin, tissue plasminogen activator (t-PA), renin, calcitonin, enkephalin, erythropoietin (EPO)~, prostaglandins, steroids and vitamins (e.g. vitamin D). Many of the peptide -protein type active substances are unstable to heat and organic solvents.
(2) Anticancer agents (e.g. mitomycin, adriamycin, cisplastin).

(3) Antibiotics (e.g. ~-lactam antibiotics, erythro-mycine amphotericin, polymixin), and so on.
Two or more drugs may be used in combination. When two drugs are used combinedly, for instance, both the drugs may be incorporated in layers A. Of course, it is ~3~ 6 possible to incorporate one drug in ]ayers A and another in layers B. In the latler case, drug release as a whole becomes continuous but, for the respective drugs, the release is pulsewise. In the case of combined use of two drugs, it is furtller possible to incorporate them in layers A alternatingly, for example, a first drug in layer la, a second drug in layer lb, the first drug in layer lc and the second drug in layer ld, as shown in Fig.
1. Referring to Pig. 1, it is also possible to incor-porate four different drugs in layers A, namely layers la, lb, lc and ld, respectively.
The mode of drug incorporation includes, among others, direct incorporation of a drug itself in polymeric material layers and incorporation of a drug enclosed in minute particles. In the former case, the drug incorpora-tion can be effected, for example, by mere admixing of a drug with a polymeric material which is to constitute drug-containing laYers, or by dissolving a drug in water, conducting Iyophilization and mixing the lyophilizate with a polymeric material, or by dissolving a drug and a polymeric material together in water, followed by lyophilization. In the latter case, the drug incorpora-tion can be realized, for example, by mixing a drug enclosed in minute partlcles with a polymeric material, or by suspending drug-containing microcapsules in a high ;

.. . . . . . . . . . . .

~ 3~016 concentration solution of a polymeric material followed by immediate Iyophilization. No particular limitations are placed on the minute particles provided that said particles should meet the following reqllirements: that they should be pharmacologically acceptable, that the drug in question should be enclosable therein and that they should be disintegrable in body fluids to there6y release the drug enclosed therein. Preferable particle sizes generally lie within the range of about 17 nm to about 1~000 /~ID~ preferably within the range of about 100 nm to about 100 ~.,.. ~oncrete examples are liposome, micro-capsules and microspheres.
Enclosure of a drug in minute particles results in stabilization of the drug, improved maintenance of the pharmacological effect or effects and more definite pulse pattern.
Drug stabilization is particularly important when the active drug substance is an unstable protein, for instance. Localization resulting from enclosure in minuSe particles as well as close coexistence within minute particles with a stabilizer suited to the drug (e.g. albumin, cholesterol, sodium benzoate) can promote the stabilization, Enclosure in minute particles can prevent possible drug deactivation, for instance, result-ing from interaction between two or more drugs contained , . . . . . . . . . . . . . . . .. . .

~3000~6 in the same or different polymeric material layers or between a dr tl g and the polymeric materia'l or materials forming polymeric material layers.
The use of a drug enclosed in minute particles thus a b ~hæ
L3 results in prolonged duration of drug efficacy and ~
duration can be adjusted in connection with the intended pulse by selecting the kind and size of minute particles for drug enclosure.
When the drug is an active trace substance, for instance, it is very difficult to achieve definite pulse-wise release of the drug in very small amounts. By enclosing such drug in minute particles together with a known vehicle and disintegrater (e,g, mannitol, sucrose, sodium hydrogen carbonate, starch, carboxymethylcellulose), however, it becomes possible to promote drug release and render the pulse more definite, The method of preparing such drug-containing minute particles is not limited to any special one. Ge'nerally employable methods are described in J. Mol. Biol., 13, 238-252 (1965) and "Microcapsules-Manufacture, Properties and Applications (1977)N, for instance. Drug-containing layers can be produced by admixing drug-containing micro-capsules witb a polymeric material, followed by layer formation.
The drug content in each layer maY suitably be ~3~10016 selected depending on the kind of drug, the kind of po}Y-meric material, and so forth. Layers B may contain the drug, which is contained in layers A, in slight amounts.
The term ~'in slight amounts" should not be construed strictly but is used to mean relative slightness as compared with the drug amount in layers A. Thus, when a drug which can produce its pharmacological effect or effects only in large doses is used, relatively large amounts in which the drug is contained in layers B fall within the meaning of the term Uslight amounts" as used herein if said relat;vely large amounts are still slight when compared with the drug amounts in layers A~
The means of producing laminate-type pharmaceutical preparations by alternatingly disposing layers A and layers B is not particularly limited. Meanwhile, accord-ing to the description in the specification to Japanese ~ /ne~ nt ~l p"'b llca~lonPatent ~}i~ ~4~ under No. 120618/81, laminate-type pharmaceutical preparations are prepared by using thermal denaturation of naturally occurring polymeric material, by application of synthetic polymeric materials using an organic solvent or solvents, or by radiation-initiated polymerization of vinyl monomers. However, these methods have problems, for example, in that they cannot be applied to those cases in which the drug or drugs are unstable to heat or radiation or that residual ~3~0~ 6 organic solvents may cause adverse reactions. Therefore, the presenl inventors recommend the compression moldin~
method as a method free from the problems involved in the production method described in the specification to ne~ ~A b 11 cO~/ an Japanese Patent ~ it~ e~4~,under No. 120618/~1.
~ ..~
The proposed method comprises forming layers A and layers B by compression molding of the respective ingredient mixtures to give the pharmaceutical preparations accord-in~ to the invention. In accordance with an embodiment of the method, a layer A is first formed by compression molding and then a layer B is formed on said layer ~ by compression molding, fol~owed by repeated formation of a layer A and a layer B in the same manner. In accordance with another embodiment, layers A and layers B prepared separately In advance by compression molding are laminat-ed together with or without preliminary appropriate adhesion. Thus, for instance, a powder-form polymeric material is compression-molded on a compression molding machine, preferahly at a pressure of 100-2000 kg/cmZ. a mixed powder composed of a drug and a polymeric material is placed on the resultant layer and`compression-molded in the same manner. These procedures are repeated until a laminate structure (laminate-type preparation) is ohtained.
A pharmaceutical preparation in which layers A

. .

~3~()0~6 contain a drug and layers B contain another ~rug, for instance, can also be produced in the same manner as above.
In this way the pharmaceutical preparations accord-ing to the invention can be prepared in a simple ancl easy manner and at the same time inactivation of drugs and adverse reactions due to residual organic solvents can be prevented.
The pulse frequency or interval and the pulse width can be adjusted by varying the number of drug-contain;ng layers and of drug-free layers ~which may contain drugs in slight amounts), the thickness of each layer, and so ~ h~
forth. ~ pulse parameters may suitably selected depending on the k-nd of drug, treatment schedule and physiological condition of the patient, among others.
The pharmaceutical preparations according to the invention can be obtained by coating the thus-obtained laminate-type preparations with a polymeric material C
~ he by a conventional method. ~or example, when ~ i poly-meric material C is a silicone elastomer, which is a typical example, such as Silastic~ 3~2 (~ow Corning~, the silicone base and the catalyst stannous octoate (about 2 drops per 10 g of silicone base) are quickly mixed and the laminate-type preparations are immersed in the mixture or the mixture is applied to the laminate-type ~o~

preparations in the manner of pain-ting, whereby the purpose of coating can be accomplished.
In the above coating stepr all the surface extending in the direction perpendicular to the layer plane is coated.
Preferably, one of the surfaces extending in the direction parallel to the layer plane (i.e. that face rom which drug release is not intended) is also coated.
The pharmaceutical preparations according to the invention arè embedded beneath the skin in a particularly preferred embodiment. Thus, the drug is released pulsewise from the face having no polymeric material coating (i.e. drug release face).
Referring to the drawings, some examples of the pulse-wise release pharmaceutical preparation according to the invention are now described.
Fig. 1 shows, in vertical section, an embodiment of the pulsewise release preparation according to the invention, in which a laminate-type preparation composed of alternatingly disposed layers ~, namely layers (la), (lb), (lc) and (ld), and layers B, namely layers ~2a), (2b) and t2c), is coated with a layer (3) of a polymeric material C on the whole surface extending in the direction perpendicular to the layer plane and on the face which extends ..

in the direction paraliel to the layer plane and drug release from which is not intended. In this example, the following modes, for instance, may be mentioned: layers A
(la), (lb), (1c) and (ld) contain a drug X while layers B
(2a), (2b) and (2c) contain no drug at all (mode 1);
layers A (la), (lb), (lc) and (ld) contain a drug X while layers B (2a), (2b) and (2c) contain another drug Y which is different from the drug X (mode 2): layers A (la), (lb), (lc) and (ld) contain a drug X and layers B (2a), (2b) and (2c) contain the drug X in slight amounts (mode 3).
~ ig, 2 shows the same embodiment as shown in ~ig. 1 except that layers A contain the drug enclosed in minute particles.
A further example shown in Fig. 3 is the same as that shown in Fig. 1 except that only the whole surface extending in the direction perpendicular to the layer plane is covered with a layer (3~) of a polymeric material C, with both the faces extending in the direction paralIel to the layer plane being free of such coating.
The geometry of the pharmacelltical preparation 1~ ~he according to the invention is optional provided that~
preparation is possessed of the constituent elements of the invention and that the object of the invention can be accomplished. For example, the preparation may be in the form of a cylinder, trigonal prism or tetragonal prism.

~L3000~1L6 In the example shown in Fig. 1, the drug is released D after administration Or ~ pharmaceutical preparation from the layer (la) and quickly glves a therapeutic con-centration and then the drug release is discontinued.
After the lapse of a certain time required for the dis-solution of the layer t2a) or for the migration of the drug from the layer (lb) through the layer (2a), the drug contained in (lb) is released to quickly give a therapeu-tic concentration. The embodiment shown in Fig. 2 makes it possible to effect drug stabilizalion and to render the pulsewise release pattern more definite since the drug is contained in minute particles. In the embodimsnt shown in Fig. 3, the drug is released pulsewise from both the faces extending in the direction parallel to the layer plane.

example 1 mixture of 15 mg of atelocollagen and 1 mg of GRF
29) was compression-molded on a tableting machine ~400 kg/cmZ) and 35 mg of alelocollagen was again compression~
molded thereon. Thus were produced a GRF(1-29)-contain-ing collagen layer and a GRF-free collagen layer. The above whole procedure was repeated three more times, so that four layers each were formed. h cylindrical pellet having a thichness of 1.3 mm, a diameter of 10 mm and a weight of 188 mg was thus produced. Separately, about 10 ' .

.

3~ 6 - lo -g of Silastic~ 382 silicone base and about 2 drops of stannous octoate were mixed together quickly. The mix-ture was placed in a vessel with a dia~meter Or 15 mm and a depth of 5 mm. The above laminated cylindrical pellet was immersed in said mixture with the bottom (GRF-contain-ing collagen layer) being left in contact with air. The silicone polymer was cured by allowing the mixture with the pellet immersed therein to stand at room temperature for 24 hours. Thereafter the whole was taken out of the vessel. The dissolution of GRF from the coated pharmaceu-tical preparation thus obtained was determined using physiological saline at room temperature and sampling the saline at timed intervals for determining the quantity of GRF released within a unit time by high-performance liquid chromatography. The results obtained are shown in ~ig. 4.
Example 2 Preparation of interferon-containing gelatin micro-spheres;
Gelatin (2.5 g) was dissolved in 37.5 ml of water and, at 40~C, 5 ml of an ~-interferon solution ~about 3 MV/ml) was added with stirring. Further, at the same temperature, 50 ml of warmed ethanol (40C) was added dropwise. After completion of the dropping, the reaction mixture was poured into 500 ml of cooled 30~ ethanol (5 ~3~001~;

C) with stirring and the whole mixture was stirred for 30 minutes. The prec;pitate was collected by centrif-ugation and cooled to 5C, The precipitate was added to 500 ml of isopropanol, the mixture was stirred for 20 minutes, and the solid matter was collected by filtration using a glass filter, washed with 500 ml of cold ethanol and then dried to give about 1 ~ of interferon-containing microspheres. Radio-immunoassay revealed that this product contained 3710 U/mg of ~-interferon, Preparation of pulsewise release preparation:
~ 4-mg portion of the above ~-interferon-containing gelatin microspheres was admixed with 15 mg of atelo-collagen. The mixture was compression-molded on a tableting machine (~00 kg/cm2) and 35 mg of atelocollagen was again compression-molded thereon, whereby a collagen layer containing the ~-interferon-containing gelatin microspheres and a collagen layer free of such micro-spheres were forlned. After three more repetitions of the above double molding process, there was obtained a cylindrical pellet having a thickness of 1.3 mm, a diam-eter of 10 mm and a weight of 198 mg and composed of four drug-containing layers and four drug-free layers. Then, in the same manner as in Example 1, the pellet was coated with the same silicone polymer except for one release ~;~000~6 face (collagen layer containing the ~-interferon-containing gelatin microspheres). The thus-obtained pharmaceutical preparation was tested for dissolution of ~-interferon therefrom at ordinary temperature usin.g ~BS
buffer containing 0.5% human serum albumin, Sampling was made at timed intervals and the quantity of ~-interferon released within a unit time was determined by radioimmuno-assay. The results obtained are shown in Fig, 5.
The pharmaceutical preparation according to the invention is advantageous in that the drug release i9 effected only from one or both faces thereof extending in the direction parallel to the layer plane, so that sustained pulsewise drug release can be attained.
The invention has been fully described in the fore-going description and examples included thereln, but they may be altered or modified in various ways without depart-ing from the spirit and scope of this invention~

Claims

1. A sustained pulsewise-release pharmaceutical preparation adapted for subcutaneous administration embedded beneath the skin and capable of releasing a drug over a prolonged period of time, which comprises a) drug-containing polymeric material layers (layers A) and polymeric material layers free from or substantially free from the drug contained in the layers A but optionally containing a drug different from that contained in the layers A (layers B) disposed alternatively in a laminated structure, and b) a surface extending in a direction perpendicular to the layers and coated in its entirety with a polymeric material which is insoluble or scarcely soluble in water and in body fluids.

2. A pharmaceutical preparation according to claim 1, wherein the layers B contain no drug at all.

3. A pharmaceutical preparation according to claim 1, wherein the layers B contain a drug which is different from the drug contained in layers A.

4. A sustained pulsewise-release pharmaceutical preparation adapted for subcutaneous administration embedded beneath the skin and capable of releasing a drug over a prolonged period of time, which comprises a) drug-containing polymeric material layers (layers A) and polymeric material layers free from or substantially free from the drug contained in the layers A but optionally containing a drug different from that contained in the layers A (layers s) disposed alternatively in a laminated structure, and b) the whole surface extending in a direction perpendicular to the layer plane and one surface in a direction parallel to the layer plane are coated with a polymeric material which is insoluble or scarcely soluble in water and in body fluids.

5. A pharmaceutical preparation according to claim 4, wherein the layers s contain no drug at all.

6. A pharmaceutical preparation according to claim 4, wherein the layers B contain a drug which is different from the drug contained in layers A.

7. A pharmaceutical preparation according to claim 1 or 4, wherein at least layers A or layers B comprise at least one member of the group consisting of collagen, gelatin, polylactic acid, polyglycolic acid and poly(lactide-co-glycolide).

8. A pharmaceutical preparation according to claim 1 or 4, wherein the polymeric material which is insoluble or scarcely soluble in water and in body fluids is a silicone polymer and covers the surface extending in a direction perpendicular to the layer plane and/or that extending in the direction parallel to the layer plane.

9. A pharmaceutical preparation according to claim 1, wherein the drug is contained in the polymeric material layers in the form of enclosed particles.

10. A pharmaceutical preparation according to claim 4, wherein the drug is contained in the polymeric material layers in a form of enclosed particles.

11. A pharmaceutical preparation according to claim 9 or 10, wherein the particles are liposomes, microcapsules or microspheres.

12. A pharmaceutical preparation according to claim 1, wherein the drug is a drug which is advantageously administered pulsewise.

13. A pharmaceutical preparation according to claim 4, wherein the drug is a drug which is advantageously administered pulsewise.

14. A pharmaceutical preparation according to claim 12, wherein the drug is a biologically active trace substance, an anticancer agent or antibiotic.

15. A pharmaceutical preparation according to claim 13, wherein the drug is a biologically active trace substance, an anticancer agent or antibiotic.

16. A pharmaceutical preparation according to claim 14, wherein the biologically active trace substance is at least one member selected from the group consisting of peptide protein type active substance, prostaglandin, steroid and vitamin.

17. A pharmaceutical preparation according to claim 15, wherein the biologically active trace substance is at least one member selected from the group consisting of peptide protein type active substance, prostaglandin, steroid and vitamin.

18. A pharmaceutical preparation according to claim 16 or 17, wherein the peptide or protein type active substance is GRF(1-29).

19. A pharmaceutical preparation according to claim 16 or 17, wherein peptide protein type active substance is interferon.

20. An implantable pharmaceutical preparation according to claim 1 or 4, wherein the layers A and layers B are formed by compression molding.

21. A pharmaceutical preparation according to claim 16 or 17, wherein the biologically active trace substance is a peptide or protein active substance for embedded use unstable to heat and organic solvents.

22. A pharmaceutical preparation according to any one of claims 1 to 6, wherein the polymeric material, the layers A and B, is degradable in living organisms over the prolonged period of time and the polymeric material of the surface coating is physiologically acceptable and is capable of serving as a coating for the laminated structure until a disintegration of the layers A and B in the living organisms is complete.

23. A sustained pulsewise-release pharmaceutical preparation being adapted for subcutaneous administration by embedding in-to the human body and being capable of releasing a drug over a prolonged period of time in a regular pulsewise pattern, which comprises:
a) a laminated structure composed of layers made of a polymeric material which contains a drug and is pharmacologically acceptable and degradable in the human body within such that the drug contained therein is released over the prolonged period of time (layers A) and layers made of a polymeric material which is free from or substantially free from the drug contained in the layers A but may contain a drug different from that contained in the layers A (layers B) disposed alternatively, wherein the drug is a member selected from the group consisting of peptide or protein type active substances, and b) a surface extending in a direction perpendicular to the layers A and B and coated in its entirety with a polymeric material which is physiologically acceptable and is so insoluble or only scarcely soluble in water and in body fluids that the polymeric material is capable of serving as a coating for the layers A and B until a disintegration of the layers A and B into the human body is complete.

24. A pharmaceutical preparation according to claim 23, wherein the polymeric material of the surface coating is a silicone elastomer.

25. A sustained pulsewise-release pharmaceutical preparation being adapted for subcutaneous administration by embedding into the human body and being capable of releasing a drug over a prolonged period of time in a regular pulsewise pattern, which comprises:
a) a laminated structure composed of layers made of a polymeric material which contains a drug and is pharmacologically

26 acceptable and degradable in the human body within such that the drug contained therein is released over the prolonged period of time (layers A) and layers made of a polymeric material which is free from or substantially free from the drug contained in the layers A but may contain a drug different from that contained in the layers A (layers B) disposed alternatively, wherein the drug is a member selected from the group consisting of peptide or protein type active substances, and b) the whole surface extending in a direction perpendicular to the layer plane and one surface in a direction parallel to the layer plane are coated with a polymeric material which is physiologically acceptable and is so insoluble or only scarcely soluble in water and in body fluids that the polymeric material is capable of serving as a coating for the layers A and B until a disintegration of the layers A and B into the human body is complete.

26. A pharmaceutical preparation according to claim 25, wherein the polymeric material of the surface coating is a silicone elastomer.