JP2641755B2 - Control release formulation - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical preparation used in the medical and livestock fields, and more particularly, to a controlled release preparation (controlled release preparation) capable of appropriately controlling the release of an active ingredient. It is about.

Conventional technology and problems The long-term sustained release of active ingredients from pharmaceutical preparations is useful for improving the therapeutic effect by extending the duration of the effective concentration in blood, and the side effect of minimizing the maximum concentration in blood. It has been discussed from the viewpoints of reducing the number of administrations, further simplifying usage by reducing the frequency of administration, and reducing patient pain. As one of the methods, use of sustained-release preparations using a polymer substance as a carrier has been proposed, and various polymer substances as carriers have been widely studied. Polymers used for such purposes include vinyl polymers,
Silicone, polyvinyl alcohol, polypeptide, chitosan, collagen, polylactic acid, polyglycolic acid and the like, among which polypeptide, chitosan, collagen, polylactic acid, polyglycolic acid and the like are preferable because they are biodegradable. It is a substance. In particular, collagen is a protein that is excellent in biocompatibility and is a particularly preferable substance because it is a protein that constitutes about 1/3 of all proteins in mammals. The present inventors have paid attention to their usefulness and have developed a sustained-release preparation using collagen, and have previously filed patent applications (JP-A-60-126217, JP-A-60-97918, JP-A-60-97918). 84213, JP-A-60-89418, JP-A-60-112713, JP-A-61-236729, and JP-A-62-230729.) However, this sustained-release preparation merely achieves sustained release over a long period of time. However, the release properties could not be appropriately controlled according to the purpose of use. That is, since a sustained-release preparation containing only a fixed amount of collagen and an active ingredient has a uniform release property, it depends on conditions such as the disease to be treated, the type of drug, and the administration period. In order to control its release properties, considerable consideration was needed.

Means for Solving the Problems The present inventors have conducted intensive studies with the aim of obtaining a sustained-release preparation capable of appropriately controlling the release of the active ingredient. It has been found that when a certain kind of acidic substance is added to an acidic preparation, the release of the active ingredient can be changed depending on the amount of the acidic substance, and the present invention has been completed based on this finding.

That is, the present invention provides, in a preparation containing collagen containing an active ingredient as a carrier, an acid selected from the group consisting of an acidic substance composed of an organic compound, and an acid anhydride or ester capable of producing the acidic substance by hydrolysis. It is intended to provide a control release preparation characterized by adding more substances.

The present invention further provides a method for producing such a control release preparation, and a method for controlling the release of an active ingredient. The term "release of the active ingredient from the preparation" as used herein is determined for the purpose of clinical effectiveness, and specifically refers to the release amount, release rate and release behavior. The release rate indicates the amount of the active ingredient released within a certain period of time, and the release behavior indicates the change of the release rate with respect to the time after administration.

That is, the present invention provides, as an active ingredient and a carrier, one or more substances selected from the group consisting of an acidic substance composed of an organic compound, and an acid anhydride or an ester capable of producing the acidic substance by hydrolysis. Characterized in that it is added to a starting material mixture containing collagen,
The present invention provides a method for producing a control release preparation exhibiting a predetermined release behavior of an active ingredient, and further provides an acidic substance comprising an organic compound, and an acid anhydride capable of producing the acidic substance by hydrolysis. Or a method for controlling the release of the active ingredient from a preparation containing a collagen containing the active ingredient as a carrier, characterized by adding one or more substances selected from the group consisting of esters. Things.

The active ingredient of the preparation of the present invention is not particularly limited, and examples thereof include biologically active substances such as prostaglandin, prostacyclin, vitamins, steroids, proteins and peptides.

The present invention is suitable for an active ingredient whose usual clinical dose is small, and is more suitable for a biologically active protein or peptide. Such biologically active proteins or peptides include, for example, cytokines, hormones, hormone releasing factors, hormone release inhibiting factors, growth factors, enzymes and the like.

Cytokines are a general term for biologically active soluble factors released when macrophages and lymphocytes are stimulated with antigens and mitogens.Those produced by lymphocytes are lymphokines, those produced by macrophages and monocytes are monokines. Called. The cytokine in the present invention is not particularly limited, and examples thereof include interferon (IFN) interleukin (IL), colony stimulating factor (CSF), macrophage activating factor (MAF), macrophage migration inhibitory factor (MIF) and the like. Can be The interferon referred to here may be any one of α, β, γ, and other interferons, and of course, a combination thereof. Similarly, the interleukin may be IL-1, IL-2 or IL-3 or any other, and the colony stimulating factor is multi-CSF
(Pluripotent CSF), GM-CSF (granulocyte-monocyte macrophage)
CSF), G-CSF (granulocyte CSF) or M-CSF (monocyte macrophage CSF), any other CSF, or a mixture thereof.

Hormones are substances that are produced and secreted by specific cells according to information inside and outside the living body and transmit the information to other cells (hormone target cells) via body fluids. The hormone in the present invention is particularly limited. Although not limited, for example, a large number such as growth hormone (GH) and calcitonin (CT) can be mentioned.

A hormone-releasing factor is a substance that directly acts on an endocrine organ to secrete a hormone. The hormone-releasing factor in the present invention is not particularly limited, but includes, for example, growth hormone-releasing factor (GRF) and luteinizing hormone (LH). −R
H). GRF is a peptide showing GH release activity, the activity of each of several peptides consisting of 44, 40, 37 or 29 amino acids has been observed,
When used in the present invention, any peptide may be used, or a mixture thereof.

The hormone release inhibitory factor is a substance that acts directly on endocrine organs to suppress the release of hormones. The hormone release inhibitory factor in the present invention is not particularly limited, and examples thereof include somatostatin and melanostatin.

Growth factors are those that promote the growth of animal cells in vivo and in vitro and are not nutrients. The growth factors in the present invention are not particularly limited, but include, for example, somatomedin (SM), nerve growth factor ( NG
F), epidermal growth factor (EGF), fibroblast growth factor (FGF), tumor growth factor (TGF), erythropoietin (EP
O) or platelet-derived growth factor (PDGF).

SM is recognized as a somatomedin group, and includes SM-A, SM-B, SM-C and insulin-like growth factor, IGF-I and IGF-II, multiplication stimulation activity (MSA) and the like. (There is also a report that SM-C and IGF-I are the same substance.) The preparation of the present invention may contain any of these alone or as a mixture.

Although the enzyme in the present invention is not particularly limited, for example, an enzyme having a thrombolytic action (eg, tissue plasminogen activator (TPA), urokinase (UK), etc.)
And the like.

As described above, the active ingredient particularly suitable for the preparation of the present invention is classified into cytokines, hormones, hormone-releasing factors, hormone-releasing inhibitors, growth factors and enzymes as biologically active proteins and peptides. Some of them have not been clearly distinguished due to their diversity in action and origin. The present invention is not limited to these classes and examples, but includes enzyme inhibitors such as tissue inhibitors of metalloproteinase (TIMP), which are collagenase inhibitors, bone morphogenetic factors (BMP), and certain antibodies. It can be widely applied to peptides, proteins, glycoproteins, etc., which are expected to be developed as pharmaceuticals in the future.

The active ingredient used in the preparation of the present invention is not limited to a specific source, and may be, for example, a substance extracted from a living body, an artificially synthesized substance, or a substance obtained by a genetic recombination method.

The acidic substance added to the control release preparation of the present invention refers to a pharmaceutically acceptable organic compound whose aqueous solution has a pH of 7 or less. Examples of such acidic substances include:
Examples include organic compounds having one or more carboxyl groups, such as citric acid, tartaric acid, succinic acid, acetic acid, and the like. Further, even those having a basic functional group, such as amino acids such as aspartic acid, glutamic acid, glycine, and alanine, may be any organic compound whose aqueous solution has a pH of 7 or less. Alternatively, all organic compounds having an aqueous solution having a pH of 7 or less, such as ascorbic acid, having no carboxyl group are included. As described above, various organic acidic compounds are applicable 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,
For example, succinic anhydride, glutaric anhydride, or lactone isocitrate can be added. The acidic substance is added for the purpose of controlling the release property, but is closely related to the release rate of the active ingredient, and the amount added is appropriately adjusted according to the desired release property. Usually, 1 to 50 in the formulation
%, About 5 to 50% for citric acid, about 5 to 45% for glycine, and about 5 to 50% for alanine.

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

Collagen used as a carrier is a protein widely distributed in the animal kingdom, vertebrates and invertebrates, and accounts for about 1/3 of all proteins in mammals.
According to recent studies, there are many types of collagen, and there are more than 10 genetically different molecular types (types) of collagen in mammals and birds, which are classified from type I to type X. Have been. The collagen used in the preparation of the present invention is not particularly limited in its origin and molecular species (type), but it is preferable to use type I collagen derived from mammals. Collagen has already been used in surgical threads, etc., and its safety is known.However, in order to further enhance safety, atelocollagen whose antigenicity has been extremely reduced by removing the telopeptide, which is the main antigenic site, is used. It may be used in the invention.

The production method of the preparation of the present invention is not particularly limited. 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 obtained powder is put into a mold and compression-molded. Alternatively, a solid solution can be obtained by spraying the mixed solution onto a mold and concentrating or drying the mixture. At this time, it can be molded into a shape suitable for an administration method and an administration site, such as a rod shape, a needle shape, a spherical shape, a disk shape, and a film shape. Alternatively, it can be produced by kneading a mixture comprising an active ingredient, collagen and an acidic substance with an appropriate amount of water or a buffer, molding the mixture into a rod or needle by injection molding or the like, and drying the mixture. Since collagen has the property of becoming fibrous and insoluble under neutral to basic conditions, acidic to neutral collagen can be used in the above production method. Since these methods do not require a special binder and do not use heat or an organic solvent, they are particularly useful for active ingredients which are unstable to these.

Although the administration method of the preparation of the present invention is not particularly limited, parenteral administration methods, in particular, excellent effects are expected by direct administration into a living body in a solid state such as injection, insertion, implantation, and placement during surgery. Is done. In addition, a film- or sheet-shaped preparation can be directly applied to the affected area, and can be used not only internally but also as an external preparation. Thus, the formulation of the present invention can have various shapes and administration methods. Therefore, not only systemic but also local use is possible depending on the expected effect.

Effect of the Invention Since the control release preparation of the present invention can be prepared to have a desired release property depending on the content of the acidic substance, it can be appropriately treated or treated for humans or livestock and is extremely useful. In addition, since the preparation of the present invention uses collagen as a carrier, it is excellent in biodegradability, and is a highly safe and excellent pharmaceutical preparation.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the present invention is not limited by these Examples and Experimental Examples.

Reference Example 1 GRF (1-
29) is uniformly mixed and stirred without causing foaming as much as possible with 7.5 ml of an aqueous solution containing 10 mg / ml, freeze-dried,
Add an appropriate amount of distilled water to swell and knead well in a mortar to obtain a homogeneous mixture. This was put into a syringe, extruded linearly from a nozzle, dried, and then cut to an appropriate length.
A columnar formulation containing 5% was obtained.

Reference Example 2 6.8 ml of an aqueous solution containing 10 mg / ml of human calcitonin was uniformly mixed and stirred with 16.6 ml of a 2 w / v% aqueous solution of atelocollagen so as to minimize foaming, freeze-dried, and then swelled by adding an appropriate amount of distilled water. And kneaded well in a mortar to obtain a homogeneous mixture. This was molded in the same manner as in Reference Example 1 to obtain a columnar preparation containing no additive and containing 17% of calcitonin based on the total weight.

Example 1 25 mg of citric acid in 20 ml of a 2 w / v% aqueous solution of atelocollagen
After mixing and mixing, 7.5 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, and then an appropriate amount of distilled water is added. Swell and knead well in a mortar to make a homogeneous mixture. This is put into a syringe, extruded linearly from a nozzle, dried, and cut into appropriate lengths to obtain a columnar preparation containing 15% of GRF and 5% of citric acid as an additive based on the total weight. Was.

Example 2 Citric acid 5 was added to 18.75 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing 0 mg, 7.5 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, and then an appropriate amount of distilled water is added. Swell and knead well in a mortar to make a homogeneous mixture. This was molded in the same manner as in Example 1 to obtain a columnar preparation containing 15% of GRF and 10% of citric acid as an additive based on the total weight.

Example 3 Citric acid 2 was added to 23.75 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing 5 mg, α-interferon 20 MU / ml
2 ml of an aqueous solution containing is uniformly mixed and stirred without foaming as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and sufficiently kneaded in a mortar to obtain a homogeneous mixed solution. This was treated in the same manner as in Example 1 and then molded into a needle to obtain a needle-shaped interferon-containing preparation containing 5% of citric acid as an additive with respect to the total weight.

Example 4 Citric acid 100m in 20 ml of a 2 w / v% aqueous solution of atelocollagen
g, and after mixing, uniformly mix and stir 2 ml of an aqueous solution containing 20 MU / ml of α-interferon as much as possible without foaming, freeze-dry, add an appropriate amount of distilled water to swell, and sufficiently in a mortar. To obtain a homogeneous mixture. This was subjected to molding treatment in the same manner as in Example 1 to obtain a rod-shaped interferon-containing preparation containing 20% of citric acid as an additive with respect to the total weight.

Example 5 Citric acid 40 was added to 14.6 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing, 6.8 ml of an aqueous solution containing 10 mg / ml of human calcitonin is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and sufficiently mortared. To obtain a homogeneous mixture. This was molded in the same manner as in Example 1 to contain 17% of calcitonin with respect to the total weight, and citric acid 10% as an additive.
% Was obtained.

Example 6 After adding and mixing 40 mg of aspartic acid to 15 ml of a 2 w / v% aqueous solution of atelocollagen, 6 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) was uniformly mixed so as not to form bubbles as much as possible. After stirring and freeze-drying, an appropriate amount of distilled water is added to cause swelling, and the mixture is sufficiently kneaded in a mortar to obtain a homogeneous mixed solution. This was molded in the same manner as in Example 1 to obtain a GRF of 15% based on the total weight and an aspartic acid of 10% as an additive.
% Was obtained.

Example 7 80 mg of aspartic acid was added to and mixed with 13 ml of a 2 w / v% aqueous solution of atelocollagen, and then 6 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) was uniformly mixed as much as possible without foaming. After stirring and freeze-drying, an appropriate amount of distilled water is added to cause swelling, and the mixture is sufficiently kneaded in a mortar to obtain a homogeneous mixed solution. This was molded in the same manner as in Example 1 to obtain a GRF of 15% based on the total weight, and aspartic acid 20 as an additive.
% Was obtained.

Example 8 160 mg of aspartic acid was added to 9 ml of a 2 w / v% aqueous solution of atelocollagen and mixed, and then GRF (1-29) was added at 10 mg / ml.
6 ml of an aqueous solution containing the mixture in the ratio described above is uniformly mixed and stirred so as not to form bubbles as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and kneaded sufficiently in a mortar to obtain a homogeneous mixed solution. This was molded in the same manner as in Example 1 to obtain a GRF of 15% based on the total weight, and aspartic acid 40 as an additive.
% Was obtained.

Example 9 Glutamic acid was added to 16 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing 20 mg, 6 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, and then an appropriate amount of distilled water is added. Swell and knead well in a mortar to make a homogeneous mixture.
This was treated in the same manner as in Example 1, and then subjected to compression molding to obtain a disk-shaped preparation containing 15% of GRF and 5% of glutamic acid as an additive based on the total weight.

Example 10 Glutamic acid was added to 15 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing 40 mg, 6 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, and then an appropriate amount of distilled water is added. Swell and knead well in a mortar to make a homogeneous mixture.
This was molded in the same manner as in Example 1 to obtain a columnar preparation containing 15% of GRF and 10% of glutamic acid as an additive based on the total weight.

Example 11 Glutamic acid was added to 13 ml of a 2 w / v% aqueous solution of atelocollagen.
After adding and mixing 80 mg, uniformly mix and stir 6 ml of an aqueous solution containing 10 mg / ml of GRF (1-29) so as to minimize foaming, freeze-dry, and add an appropriate amount of distilled water. Swell and knead well in a mortar to make a homogeneous mixture.
This was molded in the same manner as in Example 1 to obtain a column-shaped preparation containing 15% of GRF and 20% of glutamic acid as an additive based on the total weight.

Example 12 After adding and mixing 7 ml of an aqueous solution containing 10 mg / ml of glycine to 26.25 ml of a 2 w / v% aqueous solution of atelocollagen, GR was added.
10.5 ml of an aqueous solution containing 10 mg / ml of F (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and sufficiently mortared. Knead to form a homogeneous mixture. This was put into a syringe, linearly extruded from a nozzle, dried, and then cut into an appropriate length to obtain a columnar preparation containing 15% of GRF and 10% of glycine as an additive based on the total weight. .

Example 13 After adding and mixing 2 ml of an aqueous solution containing 10 mg / ml of glycine to 19.25 ml of a 2 w / v% aqueous solution of atelocollagen, GR was added.
10.5 ml of an aqueous solution containing 10 mg / ml of F (1-29) is uniformly mixed and stirred so as not to foam as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and sufficiently mortared. Knead to form a homogeneous mixture. This was put in a syringe, extruded linearly from a nozzle, dried, and cut into appropriate lengths to obtain a columnar preparation containing 15% of GRF and 30% of glycine as an additive based on the total weight. .

Example 14 Citric acid was added to 20 ml of a 2 w / v% aqueous solution of atelocollagen with 10 citric acid.
After adding and mixing 2.5 ml of an aqueous solution containing at a rate of mg / ml, GRF
7.5 ml of an aqueous solution containing (1-29) at a rate of 10 mg / ml is uniformly mixed and stirred without foaming as much as possible, freeze-dried, swelled by adding an appropriate amount of distilled water, and sufficiently kneaded in a mortar. Combine to make a homogeneous mixture. This is transferred to a mold, compressed and formed into a film, dried, and then cut into an appropriate size to obtain a film-form preparation containing 15% of GRF and 5% of citric acid as an additive based on the total weight. Obtained.

Experimental Example 1 Examples 1 and 2, GRF obtained in Reference Example 1 as a control
Each of the columnar preparations containing (1-29) was cut so as to have a length of 10 mm, and PBS (-) buffer (pH 7.4) 4 m
and leave at 37 ° C. GRF released from drug product
(1-29) is quantified by high performance liquid chromatography every 24 hours, and the cumulative release amount and release time over 3 days,
And the relationship with the amount of acid added. The results are shown in FIG. 1 and FIG.

Experimental Example 2 The columnar preparation obtained in Example 5 and the columnar preparation obtained in Reference Example 2 were each administered subcutaneously to rats as a control, and the calcitonin remaining amount in the preparation after the administration was determined every 14 days, every 1 to 4 days. It was measured. The dose is 1.7m of calcitonin per rat
g. The residual amount was measured by immediately dissolving in water after taking out the preparation from the rat, and quantifying it by high performance liquid chromatography. The results are shown in FIG.

Experimental Example 3 The columnar preparation containing GRF (1-29) obtained in Examples 12 and 13 was cut to a length of 10 mm, respectively, and
Put in 4 ml of S (-) buffer (pH 7.4) and leave at 37 ° C. Replace all buffers with each sampling
GRF (1-29) released from the formulation was quantified by high performance liquid chromatography to determine the cumulative release. The results are shown in FIG.

The results of Examples 1 and 3 above in vitro were
It shows that the active ingredient release rate from the control release preparation of the present invention is effectively controlled in accordance with the amount of the acidic substance added. Furthermore, the results of the administration experiment to rats in Experimental Example 2 show 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 indicate that the formulation of the present invention has controlled release according to the purpose of use, and has excellent pharmaceutical properties that can sufficiently meet clinical requirements. In addition, in the rat administration experiment of Experimental Example 2, a phenomenon was observed in which the addition of the additive accelerated the disappearance of the carrier itself as collagen.

[Brief description of the drawings]

FIG. 1 is a graph showing the cumulative amount of GRF (1-29) released in Experimental Example 1, wherein the vertical axis indicates the cumulative amount of GRF in the formulation before release.
(1-29) Percentage (%) with respect to the content, the horizontal axis indicates the release time (days), ▲ indicates Example 1, Δ indicates Example 2, ●
Shows the results of the preparation obtained in Reference Example 1, respectively. Second
The figure shows that in Experimental Example 1, the amount of citric acid added to the preparations produced in Examples 1 and 2 and Reference Example 1 and the accumulation of GRF (1-29) released by day 3 of the release test It is a graph which shows the relationship of the amount of release. FIG. 3 is a graph showing changes in the average amount of residual calcitonin in the preparation after subcutaneous administration in rats of Experimental Example 2, wherein the vertical axis represents the amount of calcitonin remaining in the preparation (%), and the horizontal axis represents the time after administration ( Days), and Δ indicates the results of the preparation obtained in Example 5, and ● indicates the results of the preparation obtained in Reference Example 2. FIG. 4 is a graph showing the cumulative release amount of GRF (1-29) in Experimental Example 3. The vertical axis indicates the cumulative release amount as a percentage (%) with respect to the GRF (1-29) content in the preparation before release. , The horizontal axis represents the release time (days), Δ represents Example 12, and ● represents Example.
13 shows the results of the preparation obtained in step 13, respectively.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication A61K 47/12 A61K 37/43 47/14 37/48 (72) Inventor Nobuhiko Tamura Higashi Osaka-shi, Osaka Sumitomo Pharmaceutical Co., Ltd. 2-42, Doshu-cho, Ward (72) Inventor Yoshihiro Takada 1-345 Kuragakiuchi, Ibaraki City, Osaka Prefecture Sumitomo Pharmaceutical Co., Ltd. No. 3-45 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Miho Maeda 1-3-45 Kuragakiuchi, Ibaraki-shi, Osaka Sumitomo Pharmaceutical Co., Ltd.

Claims (10)

(57) [Claims] 1. A preparation comprising a collagen containing an active ingredient as a carrier, wherein one or more selected from the group consisting of an acidic substance comprising an organic compound and an acid anhydride or ester capable of producing the acidic substance by hydrolysis. A control release preparation characterized by adding more substances. 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 selected from the group consisting of cytokines, hormones, hormone releasing factors, hormone releasing inhibitors, growth factors and enzymes.
4. The preparation according to claim 3, wherein the preparation is at least one substance. 5. The biologically active protein or peptide is interleukin, interferon, colony stimulating factor, growth hormone, calcitonin, growth hormone releasing factor, luteinizing hormone releasing hormone, somatostatin, somatomedin, nerve growth factor, epidermal growth factor, The preparation according to claim 3, wherein the preparation is a tumor growth factor, fibroblast growth factor, erythropoietin, platelet-derived growth factor, tissue plasminogen activator or urokinase. 6. The preparation according to claim 1, wherein the acidic substance has a carboxyl group. 7. The preparation according to claim 6, wherein the acidic substance is an amino acid whose aqueous solution has a pH of 7 or less. 8. The method according to claim 8, wherein the acidic substance is aspartic acid, glutamic acid, glycine, alanine, citric acid, ascorbic acid,
The formulation according to claim 1, which is a substance selected from the group consisting of tartaric acid, succinic acid, and acetic acid. 9. An active ingredient and a carrier comprising one or more substances selected from the group consisting of an acidic substance composed of an organic compound and acid anhydrides or esters capable of producing the acidic substance by hydrolysis. A method for producing a control release preparation exhibiting a predetermined active ingredient release behavior, characterized by being added to a starting material mixture containing collagen. 10. Addition of one or more substances selected from the group consisting of an acidic substance composed of an organic compound and acid anhydrides or esters capable of producing said acidic substance by hydrolysis. A method for controlling the release of the active ingredient from a preparation containing a collagen containing the active ingredient as a carrier.