JPH02710A - Control release pharmaceutical - 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 Field of Industrial Application The present invention relates to pharmaceutical preparations used in the medical and livestock fields, and more specifically to controlled release preparations (controlled release preparations) that can appropriately control the release properties of active ingredients. It is related to.

Prior art and problems The usefulness of slow-release of active ingredients from pharmaceutical preparations over a long period of time is to improve the therapeutic effect by extending the duration of the effective concentration in the blood, and to reduce side effects by suppressing the maximum blood concentration to the necessary minimum. Discussions have been made from the viewpoints of reducing the pain of patients, simplifying administration by reducing the frequency of administration, and alleviating patient pain. As one of the methods, the use of sustained release preparations using polymeric substances as carriers has been proposed, and various polymeric substances have been widely studied as carriers. Examples of polymers used for such purposes include vinyl polymers, silicones, polyvinyl alcohol, polypeptides, chitosan, collagen, polylactic acid, and polyglycolic acid, among which polypeptides, chitosan, collagen, polylactic acid, Polyglycolic acid and the like are considered preferable substances because they are biodegradable. Above all,
゛Collagen is about 1/3 of the total protein in I'ili mammals.
It has excellent biocompatibility because it is a protein that makes up
It can be said that it is a particularly preferable substance. The present inventors realized its usefulness, developed a sustained-release preparation using collagen, and filed a patent application (Japanese Patent Application Laid-Open No. 60-126217,
0-97918, JP-A-6084213, JP-A-60-
89418, JP-A-60-112713, JP-A-61-
236729 and Japanese Patent Application Laid-open No. 62-230729゜) However, although this sustained-release preparation merely achieved sustained release over a long period of time, it was not possible to appropriately control the release properties depending on the intended use. . Immediately, 1st month
Sustained-release preparations containing fixed amounts of collagen and active ingredients have uniform release characteristics, so the release characteristics may vary depending on the target disease, type of drug, administration period, etc. Considerable consideration had to be given to adjusting the release properties.

Means for Solving the Problems The present inventors have conducted intensive research with the aim of obtaining a sustained-release preparation that can appropriately control the release properties of the active ingredient, and have developed a sustained-release formulation using collagen containing the active ingredient as a carrier. It was discovered that when a certain acidic substance is added to a sex preparation, the release properties of the active ingredient can be changed depending on the addition of the acidic substance, and based on this knowledge, the present invention was completed.

That is, the present invention provides a preparation using collagen as a carrier containing an active ingredient, which contains an acidic substance consisting of an organic compound, and one or more selected from the group consisting of acid anhydrides or esters that can produce the acidic substance by hydrolysis. The present invention provides a controlled release preparation characterized by the addition of more than one substance.

The present invention further provides methods for producing such controlled release formulations, as well as methods for controlling the release of active ingredients). The release property of the active ingredient from the formulation as used herein is determined for the purpose of clinical effectiveness, and specifically refers to the release amount, release rate, and release behavior. Release rate refers to the amount of active ingredient released within a certain period of time, and release behavior refers to the change in release rate over time after administration.

That is, the present invention uses, as an active ingredient and a carrier, one or more substances selected from the group consisting of an acidic substance consisting of an organic compound, and an acid anhydride or an ester that can produce the acidic substance by hydrolysis. The present invention provides a method for the production of controlled release formulations exhibiting a predetermined release behavior of active ingredients, characterized in that they are added into a starting material mixture containing collagen, and furthermore the present invention provides Collagen containing an active ingredient is used as a carrier, characterized in that one or more substances selected from the group consisting of an acidic substance and an acid anhydride or an ester capable of producing the acidic substance by hydrolysis are added thereto. The present invention provides a method for controlling the release of the active ingredient from the formulation.

The active ingredients of the preparation of the present invention are not particularly limited, but include, for example, prostaglandin, prostacyclin,
Biologically active substances such as vitamins, steroids, proteins or peptides may be mentioned.

The present invention is suitable for active ingredients for which the usual clinical doses are small, and more particularly for biologically active proteins or peptides. Such biologically active proteins or peptides include, for example, cytonophins, hormones, hormone release factors, hormone release inhibitors, growth factors, enzymes, and the like.

Cytokine is a general term for biologically active soluble factors that are released when macrophages and lymphocytes are stimulated with antigens or mitogens.Those produced by lymphocytes are lymphokines, and those produced by macrophages and monocytes are called monocytokines. It is called force-in. Cytokines in the present invention are not particularly limited, but include, for example, interferon (■FN), interleukin (IL), colony stimulating factor (C3F), macrophage activating factor (MA
F), macrophage fugue inhibition factor (MIF), and the like. Note that interferon here refers to α,
Of course, any interferon such as β, γ, etc. may be used, or a combination thereof may be used. Similarly, the interleukin may be IL-1, IL-2 or IL-3, and the colony stimulating factor may be multi-C3F (pluripotent C3F), CM
-C3F (granulocyte-monocyte macrophage C3F), G-
C3F (granulocyte C3F) or M-C3F (monocyte macrophage C3F), any other C3F may be used,
A mixture of these may also be used.

Hormones are substances that are produced and secreted by specific cells in response to internal and external information, and transmit that information to other cells (hormone target cells) through body fluids. For example, growth hormone (GH), calcitonin (CT), etc.
I can list many.

Hormone-releasing factors are substances that act directly on endocrine organs to secrete hormones, and the hormone-releasing factors in the present invention are not particularly limited, but include, for example, growth hormone-releasing factor (GRF) and luteinizing hormone-releasing hormone. (LI-1-RH) and the like. GRF is G
It is a peptide that exhibits l-1 release activity, and activity has been recognized for several types of peptides consisting of 44, 40, 37 or 29 amino acids, but when used in the present invention, any peptide may be used; It may be a mixture of.

A hormone release inhibitor is a substance that acts directly on endocrine organs to suppress the release of hormones, and the hormone release inhibitor in the present invention is not particularly limited.
Examples include somatosfucin and melanostaten.

Growth factors are substances that promote the growth of animal cells in vivo and in vitro, and are not nutritional substances. Growth factors in the present invention are not particularly limited, but include, for example, somatomedin (SM), nerve growth, etc. factor(
NGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), tumor growth factor (TGF), erythropoietin (EPO) or platelet-derived growth factor (PDG)
F) and many others.

SM is recognized as a somatomedin group, and includes SM-AXSM-B, SM-C, insulin-like growth factors, IGF-1, IGF'-It, and multiplication stimulating activity (MSΔ). (SM-C and IGF-1
There are also reports that they are the same substance). The formulation of the present invention may contain any of these alone or as a mixture.

The enzyme used in the present invention is not particularly limited, but includes, for example, enzymes having face thrombolytic activity (eg, tissue plasminogen activator (TPA), urokinase (UK), etc.).

In the above, examples of biologically active proteins and peptides, which are active ingredients particularly suitable for the preparation of the present invention, are classified into cytokines, hormones, hormone-releasing factors, hormone-releasing factors, growth factors, and HY elements. However, some of these are not clearly differentiated due to the diversity of their actions and origins. The present invention is not limited to these categories and examples thereof, but includes enzyme inhibitors such as collagenase inhibitors, tissue inhibitors of metalloproteinases (TIMPs), bone morphogenetic factors (BMl
)), or certain antibodies, and can be widely applied to peptides, proteins, and glycoproteins that are expected to be developed as pharmaceuticals in the future.

These active ingredients used in the preparations of the present invention are not limited to a specific origin, and may be, for example, substances extracted from living organisms, artificially synthesized substances, or those obtained by recombinant methods.

The acidic substance added to the controlled release preparation of the present invention refers to an organic compound whose aqueous solution has a pH of 7 or less and is pharmaceutically acceptable. Examples of such acidic substances include:
Examples include organic compounds having one or more carboxyl groups such as citric acid, tartaric acid, succinic acid, and acetic acid. Further, even if the organic compound has a basic functional group such as an amino acid such as aspartic acid, glutamic acid, glycine, or alanine, an organic compound whose aqueous solution has a pH of 7 or less may be used. Alternatively, all organic compounds whose aqueous solutions have a P tl of 7 or less, such as ascorbic acid, are included even if they do not have a carboxyl group.

As described above, various organic acidic compounds can be used in the present invention, and among them, citric acid is preferred.

In addition to these acidic substances, acid anhydrides and esters that can produce acidic substances by hydrolysis, such as succinic anhydride, glutaric anhydride, or citric acid lactone, can also be added. The acidic substance is added for the purpose of controlling the release property, but it is closely related to the release rate of the active ingredient, and the amount added is adjusted as appropriate depending on the desired release property. Usually, 1 to 50% in the preparation, about 5 to 50% for citric acid, and 5 to 4% for glycine.
It is preferable to contain about 5%, and about 5 to 50% for alanine.

In particular, when the active ingredient is GRF, 5 to 20% for citric acid, 5 to 30% for glycine, and 5 to 20% for citric acid when the active ingredient is interferon.
In the case of glycine, it is particularly preferable to contain about 10 to 30% of citric acid, and when the active ingredient is calcitonin, it is particularly preferable to contain about 5 to 20% of citric acid.In this case, by increasing the amount of the organic acidic substance added, the amount of the active ingredient within a certain period of time can be increased. The amount released can be increased.

Collagen, which is used as a carrier, is a protein that is widely distributed in the animal kingdom, regardless of whether the animal is a mammal or not, and accounts for about 1/3 of the total protein in mammals. According to recent research, there are many types of collagen, and it has been found that there are more than 10 genetically different molecular types (types) of collagen in mammals and birds, ranging from ■ type to χ type.
classified into types. The collagen used in the preparation of the present invention is not particularly limited in its origin or molecular type (type), but it is preferable to use summer type collagen derived from mammals. Collagen is already used in surgical threads, etc., and its safety is known, but in order to further increase safety, we have developed atelocollagen, which has extremely low antigenicity by removing the telopeptide, which is the main antigenic site. May be used for inventions.

The method for producing the preparation of the present invention is not particularly limited, but for example, a mixed solution containing an active ingredient, collagen, and an appropriate amount of an acidic substance is freeze-dried and then pulverized, and the resulting powder is put into a mold and compression molded. Alternatively, a solid preparation can be obtained by placing the mixed solution in a mold and concentrating or drying it. At this time, it can be molded into a shape suitable for the administration method and site, such as a rod, needle, sphere, disk, or film. Alternatively, it can be produced by kneading a mixture consisting of an active ingredient, collagen, and an acidic substance with an appropriate amount of water or a buffering agent, molding the mixture into a rod or needle shape by injection molding, etc., and drying it. Since collagen has the property of becoming fibrotic and insoluble under neutral to basic conditions, acidic to neutral collagen can be used in the above production method. These methods do not require special binders and do not use heat or organic solvents, so they are particularly useful for active ingredients that are unstable to these.

Although there are no particular limitations on the method of administration of the preparation of the present invention, excellent effects are expected by parenteral administration, especially direct administration into living bodies in solid form, such as injection, insertion, implantation, and indwelling during surgery. be done. It is also possible to directly apply the preparation in the form of a film or sheet to the affected area, and it is possible to use it not only internally but also externally. Thus, the formulations of the present invention are available in a variety of forms and administration methods. Therefore, depending on the expected effect, it can be used not only systemically but also locally.

Effects of the Invention The Control/Lz release preparation of the present invention can be prepared to have a desired release property depending on the content of acidic substances, so it can appropriately treat or treat humans or livestock, and is extremely useful. be. Moreover, since the preparation of the present invention uses collagen as a carrier, it is an excellent pharmaceutical preparation that is highly biodegradable and highly safe.

EXAMPLES The present invention will be explained in more detail by giving Examples and Experimental Examples below. However, the present invention is not limited to these Examples and Experimental Examples.

Hair plate 1 Atelocollagen 2w/v% water solution 11121.25R
Aqueous solution 7.51Q containing σ and GRF (1-29) at a ratio of 10 mg/village was mixed and stirred uniformly without forming bubbles as much as possible, freeze-dried, added an appropriate amount of distilled water to swell, and poured into a mortar. Mix thoroughly to make a homogeneous mixture. This was put into a syringe, extruded linearly from a nozzle, dried, and then cut into appropriate lengths to obtain a cylindrical preparation containing no additives and 15% GRF based on the total ff1ffi. .

Reference Example 2 A 2 w/v % aqueous solution of atelocollagen (16.611Q) was mixed with water FJ6 containing 10ttt9/m (l) of vitrolucitonin.
Mix and stir ゜8RQ evenly without creating bubbles as much as possible, freeze-dry it, add an appropriate amount of distilled water to swell it,
Thoroughly knead in a mortar to make a homogeneous mixture. By molding this in the same manner as in Reference Example 1, a cylindrical preparation containing no additives and containing 17% calcitonin based on the total weight was obtained.

Example 1 After adding and mixing citric acid 25 and 9 to a 2w/v% aqueous solution 20H of atelocollagen, 1
7.5 μm of an aqueous solution containing a ratio of 0 mg/mσ was mixed and stirred uniformly without forming bubbles as much as possible, freeze-dried, added an appropriate amount of distilled water to swell, and thoroughly kneaded in a mortar.
Make a homogeneous mixture. This is put into a syringe, extruded linearly from a nozzle, dried, and then cut into appropriate lengths to produce a cylindrical preparation containing 15% GRF and 5% citric acid as an additive for all Llii. Obtained.

Example 2 Atelocollagen 2w/v% water 1i (M 18.75
．． After adding citric acid 50R9 to vQ and mixing, GRF
Mix and stir 7.5 ml of an aqueous solution containing (129) at a ratio of 1 Om9/m (l) evenly without creating bubbles as much as possible, freeze-dry, add an appropriate amount of distilled water to swell, and mix thoroughly in a mortar. Knead to make a homogeneous mixture.

This was molded in the same manner as in Example 1 to obtain a cylindrical preparation containing 15% GRF and 10% citric acid as an additive based on the total weight.

Example 3 Atelocollagen 2w/v% aqueous solution 1ff123.75
After adding 25 yg of citric acid to xρ and mixing, 2 mQ of an aqueous solution containing 20 MU/x12 of α-interferon was mixed and stirred uniformly without creating bubbles as much as possible. After freeze-drying, an appropriate amount of distilled water was added to swell. Thoroughly knead in a mortar to make a homogeneous mixture. This was treated in the same manner as in Example 1, and then molded into a needle shape to obtain a total of ff1ff.
A needle-shaped interferon-containing preparation containing 5% citric acid as an additive was obtained.

Example 4 After adding 100 iy of citric acid to a 2w/v% aqueous solution of atelocollagen (2OR) and mixing, a second g of an aqueous solution containing α-interferon 20MU/xQ was mixed and stirred uniformly without creating bubbles as much as possible. After freeze-drying,
Add an appropriate amount of distilled water to swell, and thoroughly knead in a mortar to make a homogeneous mixture. By molding this in the same manner as in Example 1, 20% of citric acid was added as an additive to the total weight.
A rod-shaped interferon-containing preparation was obtained.

Example 5 Atelocollagen 2w/v% water mi&14,6
After adding citric acid 40 shoulder 7 to m (1) and mixing, mix and stir 6.8 ounces of an aqueous solution containing human calcitonin 10xy/xc as much as possible without creating bubbles, freeze-dry, and add distilled water. Add an appropriate amount of to swell and knead thoroughly in a mortar to obtain a homogeneous mixture.By molding this in the same manner as in Example 1, 17% of calcitonin is added to the total weight.
% and citric acid 10% as an additive was obtained.

Example 6 After adding 40 μg of aspartic acid to 15×(l) of a 2 w/v % aqueous solution of atelocollagen and mixing, GRF(1-2
Mix and stir 6 q of an aqueous solution containing 9) at a ratio of 10 mg/zQ evenly without creating bubbles as much as possible, freeze-dry, add an appropriate m of distilled water to swell, and thoroughly knead in a mortar. Combine to make a homogeneous mixture.

By molding this in the same manner as in Example 1, total = I
A cylindrical preparation containing 15% GRF and 10% aspartic acid as an additive with respect to fffl was obtained.

Example 7 After adding and mixing 80 Rg of aspartic acid to 13 mQ of a 2 w/v % aqueous solution of atelocollagen, GRF (12
Mix and stir 6 aqueous solutions containing 9) at a ratio of 10 m9/z (l) to prevent foaming as much as possible, freeze-dry, add an appropriate amount of distilled water to swell, and thoroughly knead in a mortar. and make a homogeneous mixture.

By molding this in the same manner as in Example 1, the entire ff
A cylindrical preparation containing 5% GRFI and 20% aspartic acid as an additive with respect to 1ffi was obtained.

Example 8 After adding 160 ff9 of aspartic acid to 9 ml (l) of a 2 w/v% aqueous solution of atelocollagen and mixing, GRF
Mix and stir an aqueous solution containing (1-29) at a ratio of 10M9/C and stir it evenly without creating bubbles as much as possible.After freeze-drying, add an appropriate amount of distilled water to swell, and thoroughly mix in a mortar. Knead to make a homogeneous mixture.

By molding this in the same manner as in Example I, the total iQ
A rod-shaped preparation containing 15% GRF and 40% aspartic acid as an additive based on ffl was obtained.

Example 9 After adding 20 u of glutamic acid to 16 mQ of a 2 w/v % aqueous solution of atelocollagen and mixing,
) in a ratio of 10M9/RQ was mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, added an appropriate amount of distilled water to swell, and thoroughly kneaded in a mortar to form a homogeneous mixture. Make a mixture. This was treated in the same manner as in Example 1, and then compression molded to obtain a disc-shaped preparation containing 15% GRF and 5% glutamic acid as an additive based on the total weight.

2w/v% aqueous solution of atelocollagen 1 (ffi 15)
After adding 40o of glutamic acid to m(l and mixing, GR
Mix and stir 6 ml (l) of an aqueous solution containing F(1-29) at a ratio of 10 mg/mQ evenly without creating bubbles as much as possible, freeze-dry, add an appropriate amount of distilled water to swell, and pour in a mortar. Thoroughly knead the mixture to obtain a homogeneous mixture.This was molded in the same manner as in Example 1 to obtain a cylindrical preparation containing 15% GRF and 10% glutamic acid as an additive based on the total weight.

Example 11 Atelocollagen 2w/v% 7FJB solution 13 ttt
After adding and mixing glutamic acid 80M9 to Q, GR
6ffC of an aqueous solution containing F(1-29) at a ratio of 10 H/mQ was mixed and stirred uniformly without creating bubbles as much as possible, freeze-dried, and then swelled by adding an appropriate amount of distilled water.
Thoroughly knead in a mortar to make a homogeneous mixture. By molding this in the same manner as in Example 1, G
A cylindrical preparation containing 15% RF and 20% glutamic acid as an additive was obtained.

Aqueous solution 7 containing 2w/v% aqueous M26.25xQ of atelocollagen and glycine at a ratio of 10 mg/txQ
After adding RQ and mixing, add 10 m9 of GRF (1-29)
10.5 mg of an aqueous solution containing ρ/shoulder ρ was uniformly mixed and stirred to avoid foaming as much as possible, and then freeze-dried.
Add an appropriate amount of distilled water to swell, and thoroughly knead in a mortar to make a homogeneous mixture. This was put into a syringe, extruded linearly from a nozzle, dried, and then cut into appropriate lengths to obtain a cylindrical preparation containing 15% GRF and 10% glycine as an additive based on the total weight. .

Example 13 2w/v% aqueous solution of atelocollagen 19.2511g
Aqueous solution 21i containing glycine at a ratio of 10 mg/mQ
After adding and mixing, 10.5 mL of an aqueous solution containing GRF (1-29) at a ratio of 10 solutions/distillate was mixed and stirred uniformly to avoid creating bubbles as much as possible, and after freeze-drying, an appropriate amount of distilled water was added. The mixture is added to swell and thoroughly kneaded in a mortar to form a homogeneous mixture. This was put into a syringe, extruded linearly from a nozzle, dried, and then cut into appropriate lengths to obtain a cylindrical preparation containing 15% GRF and 30% glycine as an additive based on the total weight. .

Example 14 Aqueous solution 2.53 containing citric acid in a 2 w/v % aqueous solution of atelocollagen 2011Q at a ratio of 1 Omg/mQ
After adding 112 and mixing, add 100 GRF(1-29)
7.5 d of an aqueous solution containing 7.5 liters of water was mixed and stirred uniformly without creating bubbles as much as possible, freeze-dried, added an appropriate amount of distilled water to swell, and thoroughly kneaded in a mortar to form a homogeneous solution. Make a mixed liquid. Transfer this to a mold, compress it, form it into a film, dry it, and then cut it into appropriate sizes to obtain a mixture containing 15% GRF and 5% citric acid as an additive based on the total weight. A film-like preparation was obtained.

Experimental Example 1 Examples 1 and 2, GRF obtained in Reference Example 1 as a control (
1-29) respectively at 1-Omm.
Cut into lengths, place in PBS (-) buffer (pH 7,4) and leave to stand at 37°C. GRF (1-29) released from the formulation was quantified every 24 hours by high performance liquid chromatography, and the relationship between the cumulative release amount, release time, and acid addition m over 3 days was determined. The results are shown in FIGS. 1 and 2.

Experimental Example 2 The cylindrical preparation obtained in Example 5 and the cylindrical preparation obtained in Reference Example 2 as a control were each subcutaneously administered to rats, and the residual calcitonin m in the preparation after administration was measured every 1 to 4 days for 14 days. It was measured. The dose was 1.5 mg of calcitonin per rat.
It was administered so that the amount was 7π9. The residual volume was measured by removing the preparation from the rat, immediately dissolving it in water, and subjecting it to high performance liquid chromatography for determination. The results are shown in Figure 3.

Experimental Example 3 The cylindrical preparations containing GRF (1-29) obtained in Examples 12 and 13 were each cut into 10 mm lengths and added to PBS (-) buffer (pH 7°4).
4if2 and leave it at 37°C. The entire amount of buffer is replaced after every sampling, and G released from the preparation is
RF(1-29) was determined by high performance liquid chromatography, and the cumulative release m was determined.

The results are shown in Figure 4.

The in vitro results of Experimental Examples 1 and 3 above demonstrate that the release rate of the active ingredient from the controlled release formulation of the present invention is effectively controlled in accordance with the amount of acidic substance added. Furthermore, the results of the administration experiment to rats in Experimental Example 2 indicate that it is useful to add an acidic substance for the purpose of controlling the release of the active ingredient from the preparation even in vivo. These results demonstrate that the preparation of the present invention has a release property that is controlled according to the intended use and has excellent pharmaceutical properties that can fully meet clinical demands. In addition, in the rat administration experiment of Experimental Example 2, it was observed that the addition of additives also accelerated the disappearance of collagen itself, which is a carrier.

[Brief Description of the Drawings] Figure 1 is a graph showing the cumulative release 1n of GRF(1-29) in Experimental Example 1, where the vertical axis represents the cumulative release 1n of GRF(1-29) in the preparation before release. The results are shown in percentage (%) relative to ■, the horizontal axis represents the release time (days), M represents the results of the formulation obtained in Example 1, ■ represents Example 2, and * represents the results of the formulation obtained in Reference Example 1, respectively. FIG. 2 shows the results of Examples 1 and 2 in Experimental Example 1.
, and the citric acid mother added in the formulation manufactured in Reference Example 1 and the GRF (1-
29) is a graph showing the relationship between cumulative release m. Figure 3 shows the average residual f in the carcinogen after subcutaneous administration to rats in Experimental Example 2.
This is a graph showing the change in IL, the vertical axis shows the residual cartonnin (%) in the preparation, and the horizontal axis shows the time (days) after administration.
, ■ indicates the results of the formulation obtained in Example 5, and . indicates the results of the formulation obtained in Reference Example 2, respectively. Figure 4 shows the GRF (1
-29) A graph showing the cumulative release amount, where the vertical axis shows the cumulative release amount as a percentage (%) of the GRF (1-29) content in the preparation before release, and the horizontal axis shows the release time (days). ,
Sono indicates the results of the formulation obtained in Example I2, and * indicates the results of the formulation obtained in Example 13, respectively.

Claims (1)

[Claims] 1. A collagen-based preparation containing an active ingredient selected from the group consisting of an acidic substance consisting of an organic compound, and an acid anhydride or ester that can produce the acidic substance by hydrolysis. A controlled release preparation, characterized in that one or more substances are added thereto. 2. The preparation according to claim 1, wherein the collagen is atelocollagen. 3. The preparation according to claim 1, wherein the active ingredient is a biologically active protein or peptide. 4. The biologically active protein or peptide is one or more substances selected from the group consisting of cytokines, hormones, hormone release factors, hormone release inhibitors, growth factors, and enzymes. The formulation described. 5. The preparation according to claim 4, wherein the cytokine is an interleukin, an interferon or a colony stimulating factor. 6. The preparation according to claim 4, wherein the hormone is growth hormone or calcitonin. 7. The preparation according to claim 4, wherein the hormone-releasing factor is growth hormone-releasing factor or luteinizing hormone-releasing hormone. 8. The preparation according to claim 4, wherein the hormone release inhibitor is somatostatin. 9. The preparation according to claim 4, wherein the growth factor is somatomedin, nerve growth factor, epidermal growth factor, tumor growth factor, fibroblast growth factor, erythropoietin or platelet-derived growth factor. 10. The preparation according to claim 4, wherein the enzyme is tissue plasminogen activator or urokinase. 11. The preparation according to claim 1, wherein the acidic substance has a carboxyl group. 12. Acidic substances include aspartic acid, glutamic acid, glycine, alanine, citric acid, ascorbic acid, tartaric acid,
The formulation according to claim 1, which is a substance selected from the group consisting of succinic acid and acetic acid. 13. The preparation according to claim 1, wherein the active ingredient is growth hormone releasing factor and the acidic substance is citric acid or glycine. 14. The preparation according to claim 1, wherein the active ingredient is interferon and the acidic substance is citric acid or glycine. 15. The preparation according to claim 1, wherein the active ingredient is calcitonin and the acidic substance is citric acid. 16. Containing one or more substances selected from the group consisting of an acidic substance consisting of an organic compound, and an acid anhydride or ester that can produce the acidic substance by hydrolysis, an active ingredient, and collagen as a carrier. 1. A method for producing controlled release preparations exhibiting a predetermined release behavior of an active ingredient, characterized in that they are added to a starting material mixture containing a predetermined release behavior. 17. An active ingredient characterized by adding one or more substances selected from the group consisting of an acidic substance consisting of an organic compound, and an acid anhydride or an ester capable of producing the acidic substance by hydrolysis. A method for controlling the release of an active ingredient from a formulation using collagen as a carrier.