JPH10130171A - Pharmaceutical composition for oral administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutically stable composition for oral administration for increasing in vivo absorbability of a substance of low absorptivity by oral administration. SOLUTION: This pharmaceutically stable composition for oral administration is obtained by homogeneously dispersing effective dose of physiologically active substances of low oral absorbability, such as physiologically active peptides, particularly insulin, calcitonin, parathyroid hormone and human growth hormones, different vitamins, antiallergic agents, immunosuppresive agents, parenteral antibiotics, parenteral antimicrobial agents, osteoporosis therapeutic agents, etc., together with gastromucosa tissue restorable and protective substances or gastrointestinal function modulating substances.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition for oral administration, and more particularly, to a pharmaceutical composition for oral administration for increasing the in vivo absorption of a physiologically active substance having low absorbability by oral administration. The present invention provides, among the above-mentioned compositions, peptide hormones, bioactive proteins, bioactive peptides such as enzyme proteins, or various vitamins, antiallergic agents, immunosuppressants, parenterally administered antibiotics, parenterally administered antibacterials. Orally-administered pharmaceutical composition having excellent pharmaceutical stability and excellent bioabsorbability of a physiologically active substance in a composition when orally administered a low-absorbable drug such as an agent for treating osteoporosis. About things.

[0002]

2. Description of the Related Art Including calcitonin, insulin, parathyroid hormone (PTH), human growth hormone (HGH), luteinizing hormone-releasing hormone (LH-RH), gonadotropin-releasing hormone (GnRH) and derivatives thereof. BACKGROUND ART A bioactive peptide is a polymer compound that is used in various medical applications in the field of treatment because of its specific bioactivity. However, since these physiologically active peptides are degraded by proteases in the digestive tract, they are hardly absorbed from the gastric mucosa as they are, and therefore, oral administration is difficult, and the administration method of these drugs is limited to injection administration. . by the way,
Such a method of administration causes pain at the injection site for the patient, is not preferred, and causes significant pain to the patient when administered at regular intervals. Therefore, the development of a non-injectable administration method that is simple and easy to administer safely and frequently is desired.

[0003] As one of such administration methods, the present inventors have studied nasally administered powder preparations of these physiologically active peptides, and uniformly dispersed the physiologically active peptides in a specific carrier newly discovered by the present inventors. It has been established that the applied composition is very well bioabsorbed through the nasal mucosa when administered nasally, and a patent application has already been filed in this regard. That is, the nasal administration type powder formulation previously proposed by the present inventor has been studied as a carrier for a nasal administration formulation of a physiologically active peptide, and uses a gastric mucosal tissue repair / protective substance as a carrier. is there. These substances dissolve under acidic conditions, and also enhance mucus secretion, enhance mucosal glycoproteins and glycolipids, promote alkaline secretion, enhance mucosal blood flow, increase mucosal prostaglandin action, and promote mucosal tissue respiration. To increase
Has tissue metabolism and activation. In addition, these substances are strongly adherent to the mucous membranes, have a short flagella clearance time, and provide sustained absorption. Therefore, such a gastric mucosal tissue repair / protective agent is administered intranasally to enhance the activity of the venous plexus in the nasal mucosa lamina propria of the nasal cavity. The physiologically active peptide dispersed in is dispersed intranasally, is absorbed into the body through the nasal mucosa, enters the systemic circulatory system, and exhibits excellent absorbability in the body.

The intranasal preparations proposed by the present inventor have the same bioavailability (bioavailability) of physiologically active peptides that have been difficult to administer orally until now than those obtained with conventional injection preparations. And its clinical applicability is excellent. However, in view of the patient's QOL, development of an orally administrable formulation may also be desirable.

On the other hand, a large number of synthetic to semi-synthetic drugs have been developed for various therapeutic purposes, and have been widely used in the field of medical treatment. However,
Even among these drugs, many of them have only been developed as oral or parenteral administration preparations,
Particularly, in the case of drugs that cannot be administered orally, methods such as intravenous or intramuscular injection have been developed. In addition, some pharmaceuticals developed as oral dosage forms have low oral absorbability in actual administration and require higher doses in order to increase the therapeutic effect. is there. For example, among various antibiotics or antibacterial agents, many have low oral absorbability and must be administered by injection, and many antineoplastic agents are also injection preparations. In addition, many antiallergic drugs are generally regarded as having low oral absorbability, and among the vitamins, there are vitamins having low oral absorbability. In addition, many of the osteoporosis that have been actively developed in recent years are
Although it is a preparation for oral administration, it has been pointed out that it has poor absorbability in vivo. Therefore, it is desirable to increase the bioabsorbability of such a drug having a low oral absorbability in order to reduce the amount of the drug to be administered and to ensure more safety. At present, the development of pharmaceutical compositions for administration has been strongly desired.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition for oral administration for increasing the in vivo absorption of such a physiologically active substance having low absorbability by oral administration. . Among them, specific problems of the present invention include bioactive peptides, which are physiologically active substances having low oral absorption by oral administration, various vitamins, antiallergic agents, immunosuppressants, and parenteral antibiotics. Substances, parenteral administration type antibacterial agents, osteoporosis therapeutic agents, and the like, with the object of providing a pharmaceutical composition for oral administration to increase bioabsorbability, as a more specific problem, a bioactive peptide, Good absorbability in the body,
It is an object of the present invention to provide a pharmaceutical composition containing a physiologically active peptide, which is pharmaceutically stable and can be orally administered.

The inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, have never been studied as a carrier of an oral administration preparation of a physiologically active substance. The present inventors have newly found that the preparation substance is not only a carrier for a powder preparation for nasal absorption, but is also preferable as a powder preparation carrier (formulation base) for oral administration.

That is, the gastric mucosal tissue repairing / protecting substance as a carrier used in the present invention has an average particle diameter of 100 μm or less, and has a surprisingly porous powdery or crystalline property. Turned out to be. Therefore, physiologically active substances, particularly the physiologically active peptides calcitonin, insulin, parathyroid hormone (PTH),
When physiologically active peptides including human growth hormone (HGH), luteinizing hormone releasing hormone (LH-RH), gonadotropin releasing hormone (GnRH) and the like and derivatives thereof are uniformly dispersed with this carrier, It is considered that the bioactive peptide is encapsulated therein by utilizing the porosity of the carrier, and reaches the intestinal mucosa without being degraded by the protease in the digestive tract even when administered orally. In addition, the gastric mucosal tissue repair / protective substance, which is a carrier, enhances intestinal mucosal tissue respiration, has tissue metabolism and activation effects, has strong adhesion to mucous membranes, and is cleared by flagella. It is known that time has passed. Therefore, the physiologically active peptide homogeneously mixed with such a gastric mucosal tissue repair / protective substance or the like is preferably orally administered in the form of an enteric powder formulation to enhance the activity of the intestinal mucosa, which is the absorption site. As a result, it is absorbed into the body, enters the systemic circulatory system, exhibits excellent absorbability in the body, and achieves bioavailability equivalent to that obtained by standard injection administration. It was completed.

[0009]

Means for Solving the Problems The present invention provides an effective dose of a low-absorbable physiologically active substance by oral administration.
Provided is a pharmaceutical composition for oral administration which is uniformly dispersed together with a substance for repairing / protecting gastric mucosal tissue or a substance for regulating gastrointestinal function. In particular, a preferred embodiment of the present invention is to provide a peptide composition for oral administration in which an effective dose of a physiologically active peptide is uniformly dispersed together with a substance for repairing / protecting gastric mucosal tissue or a substance for regulating gastrointestinal function. Among them, in the present invention, it is particularly preferable that the peptide composition for oral administration is an enteric preparation.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the substance for repairing / protecting gastric mucosal tissue or the substance for regulating gastrointestinal function as a carrier for uniformly dispersing a physiologically active peptide includes, for example, drugs already used clinically. Can be Examples of such substances include gefarnate (trade name: gefanil), aceglutamide aluminum (trade name: gulmar), sucralfate (trade name: alsalmine),
L-glutamine (commercial name: gurmin), sofacolcon (commercial name: Sorone), teprenone (commercial name: Celvex), praunitol (commercial name: Kelnac), rebamipide (commercial name: Mucosta), aldioxa (commercial name: Aranta, Isalone, Ascomp, etc.), cetraxate (trade name: Neuel), troxipide (trade name: Aplace), benexate hydrochloride betadex (trade name: Urgut), thiamine-cobalt-chlorophyllin complex compound (trade name: Gaslon N), domperidone (Commercial name: nauzerin), trimebutine maleate (commercial name: cerequinone), cisapride (commercial name: acenaline), HT ₃ −
Antagonists, HT ₄ -agonists and the like. However, it is now difficult for these substances to act as a preparation carrier for the bioactive peptide, preferably uniformly dispersed as an enteric-coated preparation and, when administered orally, to absorb the bioactive peptide contained therein well in vivo. What was not known until now. The substance for repairing / protecting gastric mucosal tissue as such a carrier has an average particle diameter of 1%.
It is preferably one having a size of not more than 00 μm and having a porous powdery or crystalline structure. Further, even fine particles having an average particle diameter of 100 μm or less and having a porous powdery or crystalline structure can be used.

[0011] On the other hand, the physiologically active substances which can be improved in bioabsorbability by the pharmaceutical composition provided by the present invention include
A lower physiologically active substance absorbable by oral administration, such physiologically active peptides, various vitamins, for example cyanocobalamin, vitamin B ₁₂ derivatives such as mecobalamin, antiallergic agents, immunosuppressive agents, parenteral administration Antibiotics, parenterally administered antibacterial agents, osteoporosis treatment agents and the like. As vitamins, especially cyanocobalamin,
Vitamin B ₁₂ derivative gives a preferred result of such mecobalamin, antiallergic agents, tranilast, ketotifen fumarate, azelastine hydrochloride, oxatomide, amlexanox, repirinast, Ipujirasuto, Tazanorasuto, etc. ozagrel hydrochloride is listed, as an immunosuppressive agent , Cyclophosphamide, azathioprid, cyclosporin and the like. Further, parenteral administration antibiotics include various penicillin antibiotics, cephalosporin antibiotics, aminoglycoside antibiotics, macrolide antibiotics, and the like. Parenteral administration antibacterial agents include quinolone and It is a new quinolone antibacterial agent, and examples of the therapeutic agent for osteoporosis include bisphosphonate, alendronate, dimethylpamidronate, disodium pamidronate, risedronate, and tiludronate.

In the present invention, the oral absorbability of a physiologically active peptide can be particularly improved. Examples of such a physiologically active peptide include peptide hormones, physiologically active proteins, enzyme proteins, and opioid peptides. Such usable bioactive peptides include, for example, peptide hormones such as calcitonin, insulin, thyroid stimulating hormone releasing hormone (TRH) such as cyclovelin, luteinizing hormone releasing hormone (LH-RH)
For example, beserelin, LH-RH antagonist, adrenocorticotropic hormone (ACTH), adrenocorticotropic hormone releasing hormone (CRH) such as corticovelin, growth hormone releasing hormone (GH-RH) such as somatrelin,
Gonatropin (gonadotropin), gonadotropin-releasing hormone (GnRH) such as gonadoriverin, parathyroid hormone (PTH), growth hormone (GH) such as somatropin, prolactin (mammary stimulating hormone), follicle stimulating hormone (FSH), glucagon, vasopressin , Somatostatin (a growth hormone release inhibitor), paratormon (a parathyroid hormone), angiotensin,
Gastrin, secretin, melanocyte stimulating hormone, oxytocin, protirelin, corticotropin,
Thyrotropin (thyroid stimulating hormone), G-CSF, erythropoietin, superoxide dismutase (S
OD), opioid peptides (eg endorphin)
And so on. In addition, interferon, interleukin, urokinase, lysozyme, vaccine and the like can also be mentioned. Note that these physiologically active peptides are not limited to those described above, and may be dispersed with the specific carrier of the present invention. Needless to say.

Among the above-mentioned physiologically active peptides, peptide hormones are particularly preferred. These peptide hormones include calcitonin, insulin, parathyroid hormone (PTH), buserelin (luteinizing hormone releasing hormone: LH-RH), and somatropin. (Growth hormone:
HGH), growth hormone releasing hormone (GH-RH),
Gonatropin (gonadotropin), gonadotropin releasing hormone (GnRH) and the like are particularly preferred. Examples of calcitonin include salmon calcitonin, human calcitonin, salmon human chimera calcitonin, porcine calcitonin, chicken calcitonin, bovine calcitonin, L (eel) calcitonin, and the like. All of these calcitonins exist in nature and can be extracted. And are commercially available. In the present invention, any of these calcitonins can be used. In addition, parathyroid hormone (PTH) includes human PTH and bovine PT.
H, porcine PTH, etc., of which human PTH (1-3
4) is preferred. Gonadotropin-releasing hormone (GnRH) which promotes secretion of LH and its derivatives include buserelin acetate, and as growth hormone (GH), human growth hormone (HGH) is preferred.

Therefore, preferred specific embodiments of the present invention include calcitonin, insulin, thyroid-stimulating hormone-releasing hormone (TRH), luteinizing hormone-releasing hormone (LH-RH), somatostatin, adrenocorticotropic hormone (ACTH), adrenal gland Corticotropic hormone releasing hormone (CRH), growth hormone releasing hormone (GH-R)
H), gonadotropin (gonadotropin), gonadotropin releasing hormone (GnRH), parathyroid hormone (PTH), growth hormone (GH), somatropin, prolactin (mammary stimulating hormone), follicle stimulating hormone (FSH), glucagon, An effective dose of a peptide hormone selected from vasopressin, somatostatin (a growth hormone release inhibitory factor) and the like is determined by using gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofacalcon, teprenone, praunotor, rebamipide, aldioxa, setraxate, toloxipide. , Benexate hydrochloride betadex, at least one gastric mucosal tissue repair / protective substance such as thiamine / cobalt / chlorophyllin complex compound, or domperidone, trimebutine maleate, Sapurido, HT ₃ - antagonist, HT ₄ - with uniformly dispersed with at least one gastrointestinal function adjusting agent selected from the agonist is to provide a pharmaceutical composition for oral administration which is enteric formulation.

According to the study of the present inventors, it has been surprisingly found that the above-mentioned substance for repairing / protecting gastric mucosal tissue or a gastrointestinal function regulator has a stabilizing effect on bioactive peptides. In particular, sofalcon, a gastric mucosal tissue repair / protective substance, is particularly superior to insulin, which has been conventionally formulated only as a dissolvable injectable preparation at the time of use and is also stored in a cold place. It has been found that there is a stabilizing effect. That is, as is clear from the test examples described below, the preparation in which insulin is uniformly dispersed in sofacolcon is stable even under severe storage conditions at 40 ° C., and a ready-to-use soluble insulin injection preparation (stabilization treatment). ), The stability of which was higher than that of the formulation with about half the content in one month. In particular, the bulk of insulin
Normally, only about 10% remains in one month under severe conditions of 40 ° C., but when using Sofalcon, the survival rate is extremely high, indicating that it shows excellent stability. . Furthermore, it has been newly found that sucralfate exhibits an extremely high stability effect on a water-soluble physiologically active peptide such as calcitonin.

Accordingly, the present invention provides, as another preferred embodiment thereof, gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofacolcon, teprenone, praunitol, rebamipide, aldioxa, setraxate, troxipide, venexate hydrochloride betadex, Gastric mucosal tissue repair / protective substance selected from thiamine / cobalt / chlorophyllin complex compound, or at least one gastrointestinal function-modulating substance selected from domperidone, trimebutine maleate, cisapride, HT ₃ -antagonist, HT ₄ -agonist And a stabilizing agent for a physiologically active peptide, which is a sofalcone, which is a gastric mucosal tissue repair / protective substance as a stabilizing agent for a physiologically active peptide, particularly preferably. Offering sofalcone, a gastric mucosal tissue repair / protective agent as an insulin stabilizing agent, and Sucralfate, a gastric mucosal tissue repair / protective agent as a water-soluble bioactive peptide stabilizing agent It also does.

[0017]

The specific action of the pharmaceutical composition of the present invention in the bioabsorbability is described below based on a preferred embodiment in which a bioactive peptide is used as a bioactive substance and a gastric mucosal tissue repair / protective substance is selected as a carrier. An example of the invention will now be described.

The amount of the physiologically active peptide contained in the composition for oral administration of the present invention as an effective dose is determined by the amount of each active substance to be selected (for example, calcitonin,
Its relative activity titer, insulin units if insulin), the disease to be treated, the desired number of oral doses,
It depends on the individual therapeutic effect required. That is, when the composition of the present invention is used by oral administration, for example, it is possible to determine the therapeutic effect of a preparation containing the active substance in comparison with bioavailability with other known preparations. You can.

In the composition for oral administration as an enteric preparation of the present invention, the effective content of the physiologically active peptide is, for example, 0.0001 to 3 per 100% of the weight of the preparation.
0%, preferably 0.01 to 20%, more preferably 0.1 to 5.0%. Further, the compounding amount of the gastric mucosal tissue repair / protective substance as a carrier constituting the composition of the present invention is within the range of clinically used amount of these substances, for example, 7 per 100% of the weight of the preparation.
0-99.995%, preferably 80-99.99%,
More preferably, by blending 95 to 99.9%, good oral absorption was found to be obtained.

In order to obtain a composition for oral administration containing an effective dose of the physiologically active peptide of the present invention, a conventionally used pharmaceutical technique can be appropriately applied. For example, it can be obtained by mixing a gastric mucosal tissue repair / protective substance, which is a special carrier of the present invention, with a physiologically active peptide. For example, as an example of this mixing, a physiologically active peptide (for example, calcitonin) is added to a gastric mucosal tissue repair / protection agent (for example, sucralfate), mixed, and then a small amount of purified water is added and kneaded. Lyophilize under the conditions for about 10 to 14 hours. After the freeze-drying is completed, it can be manufactured by warming up to 30 ° C. over 3 to 5 hours, preferably about 4 hours, finally adding calcium stearate, and further kneading. Alternatively, it can be produced by a spray drying method.

In this way, a fine powder (orally administered composition) in which the physiologically active peptide is uniformly bonded to the desired substance for repairing / protecting gastric mucosal tissue is obtained. In this case, the amount of each component is not particularly limited. For example, in the case of calcitonin, the amount is 200 IU / 30 mg as a composition, and in the case of PTH (1-34), the composition is 60μg / 30mg or 90μg
/ 40 mg, and in the case of gonadotropin-releasing hormone (GnRH), the composition may be 50 μg / 30 mg. The resulting peptide composition is preferably in the form of an enteric preparation, such as an enteric capsule or the like, or a tablet, in order to avoid the influence of protease, since the absorption site of the physiologically active peptide is in the intestinal tract. After tableting, it is intended to be enteric-coated by oral enteric coating or the like, and is made into an enteric peptide composition for oral administration.

In the composition of the present invention, other excipients, stabilizers, fillers, binders, dispersants, lubricants, and adsorbents which are generally used pharmaceutically are used. Needless to say, it is also possible to add such as appropriate. In accordance with the above method, other gastric mucosal tissue repair / protective agents (for example,
Aldioxa and cetraxate) can also be subjected to the same treatment to obtain the desired compositions. Hereinafter, specific effects and specific stability effects of the peptide composition for oral administration of the present invention are shown in Test Examples.

[0023]

[Test example]

Test Example 1: Preparation of composition of the present invention: LH- as a bioactive peptide
Buserelin, which is RH, was selected, and sucralfate, which is a substance for repairing and protecting gastric mucosal tissue, was selected as a carrier base, which was used as an enteric composition for oral administration of the present invention. The content of buserelin is 300 μg / 30 mg
Were mixed and dispersed so as to obtain the composition, and the obtained mixture was filled in an enteric capsule to prepare a composition of the present invention. In addition, sucralfate as a carrier was a porous crystalline material having an average particle diameter of 17.45 μm. Oral administration absorption: The above composition was orally administered (single dose) using three cynomolgus monkeys, before administration, and after administration of 30, 45, 6
Blood was collected every 0, 120 and 150 minutes, and the blood concentration of buserelin was measured by the direct method. Table 1 summarizes the results.

[0024]

[Table 1]

As is clear from the results in the table, LH-R
It has been found that buserelin, which is H, shows effective in vivo absorption by oral administration without being degraded by proteases, which are enzymes in the digestive tract. Therefore,
The composition of the present invention, which is an enteric preparation using sucralfate which is a gastric mucosal tissue repair / protective substance as a specific carrier (formulation base), can be administered orally.
In general, it can be understood that absorption of buserelin into the blood comparable to that by injection administration is observed. In particular, in the oral administration of the composition of the present invention, the in vivo absorbability of the physiologically active peptide is sustained, and its clinical applicability is considerably better than that of an injection preparation.

Test Example 2: Preparation of the composition of the present invention: Salmon calcitonin was selected as the physiologically active peptide, and sucralfate, a substance for repairing and protecting gastric mucosal tissue, was selected as the carrier base, and the oral administration of the present invention. Composition. Both were mixed and dispersed so that the composition of salmon calcitonin was 1 mg / 200 mg, and the obtained mixture was filled in a normal capsule to prepare the composition of the present invention. In addition, sucralfate as a carrier was a porous crystalline material having an average particle diameter of 17.45 μm. Oral administration absorption: The above composition was orally administered (single) using four rhesus monkeys, and before administration, 15, 30 minutes after administration, and 1
Blood was collected every 1.5, 2, 3, 4, 5, 6, and 7 hours and serum concentration of salmon calcitonin was measured using a standard RIA kit. Accordingly, as a bioassay, pre-administration, 1, 2, 3, 4, 5, 6,
The movement of Ca ions in blood every 7 hours and the fluctuation of total Ca in serum were measured. Table 2 shows the results.
(Serum calcitonin concentration), Table 3 (movement of blood Ca ions) and Table 4 (movement of total Ca in serum).

[0027]

[Table 2]

[0028]

[Table 3]

[0029]

[Table 4]

From the results in the table, it can be seen that the composition using sucralfate, which is a substance for repairing and protecting gastric mucosal tissue as a specific carrier (formulation base) of the present invention, is filled in a usual capsule (not enteric). And still show valid in vivo bioassay data,
It has been suggested that the composition, when filled into enteric coated capsules and administered, exhibits better absorption.

Test Example 3: Preparation of composition of the present invention: PHT as bioactive peptide
(1-34) was selected, and sofalcon, a substance for repairing and protecting gastric mucosal tissue, was selected as the carrier base for the preparation, and used as the composition for oral administration of the present invention. PHT (1-3
The content of 4) was mixed and dispersed to give a composition of 600 μg / 200 mg, and the obtained mixture was filled in a normal capsule to prepare a composition of the present invention. In addition, sofalcone as a carrier was a porous crystalline material having an average particle diameter of 33.19 μm. Oral administration absorption: The above composition was orally administered (single) using two cynomolgus monkeys, and before administration, 30, 60,
Blood was collected every 90, 120, 180, 240, 300 and 360 minutes, and the blood concentration of PTH (1-34) was measured using the ELISA 1-34 PTH2 antibody method. Table 5 summarizes the results.

[0032]

[Table 5]

As is evident from the results in the table, the specific composition of the present invention, Sofalcone as a carrier,
It turns out that PTH (1-34) shows good absorption in blood by oral administration.

Test Example 4: Insulin stability test Preparation of the composition of the present invention: Insulin as a physiologically active peptide and sofalcon, a gastric mucosal tissue repair / protective substance, as a carrier of the present invention Together with the mixture to prepare a composition for oral administration of the present invention.
The insulin content is 20 capsules per capsule.
Capsule filled as IU / 20 mg. Stability test: Capsules prepared as above were
The samples were allowed to stand in a constant temperature chamber at 25 ° C., 25 ° C. and 40 ° C., and the remaining rates of insulin one month, two months, and three months thereafter were determined. The test was performed on three samples (three capsules) under each condition.
The average residual ratio when the content was set to 00% was determined. The results are shown in Table 6.

[0035]

[Table 6]

As is clear from the results in the table, it is found that sofalcone as a carrier, which is a specific composition of the present invention, has a stabilizing effect of insulin.
In particular, the storage stability under severe conditions of 40 ° C. was extremely high. The stability of bulk insulin powder is 40
Compared to the fact that there is only a residual rate of about 10% under severe conditions of ° C, it can be said that the stability action of sofacalcon is particularly excellent.

Test Example 5: Stability test of calcitonin: Preparation of the composition of the present invention: Salmon calcitonin as a physiologically active peptide, and sucralfate, a gastric mucosal tissue repair / protective substance, as a carrier base of the present invention Together with the mixture to prepare a composition for oral administration of the present invention. As a control, a composition in which salmon calcitonin was uniformly dispersed using calcium carbonate as a carrier was used. The content of salmon calcitonin, sucralfate as carrier and calcium carbonate,
It was prepared at an average of 230 IU / 20 mg per capsule and filled in capsules.

Stability test: Capsules prepared above were
The capsules were allowed to stand in a constant temperature chamber at 5 ° C. and 25 ° C., respectively, and the residual ratio of salmon calcitonin in each capsule was determined after 1 month, 2 months, 3 months, and 6 months. As a further severe test, the capsules prepared above were allowed to stand in a constant temperature chamber at 40 ° C., and the residual ratio of salmon calcitonin in each capsule after 1 week, 2 weeks, 3 weeks, 4 weeks, and 8 weeks I asked. The test was 3 under each condition.
The test was performed on a sample (3 capsules), and the average residual ratio was determined when the salmon calcitonin content at the time of preparation was 100%. Table 7 (5 ° C and 25 ° C)
And Table 8 (in the case of a severe test at 40 ° C.).

[0039]

[Table 7]

[0040]

[Table 8]

As is evident from the results in the table, it is found that sclasphert as a carrier, which is a specific composition of the present invention, has a stability effect of calcitonin, a water-soluble physiologically active peptide. When calcium carbonate is used as the carrier, a certain degree of stability is ensured even at 5 ° C. and 25 ° C., but it is rapidly decomposed under severe conditions of 40 ° C. On the other hand, it is understood that sucralfate shows extremely high specific stability.

The preparation examples of the composition of the present invention are shown below.
It is not limited to this. Powder composition 1: Calcitonin composition A calcitonin composition is produced by the following composition. Calcitonin 6540 IU Calcium stearate 60 mg Sucralfate (or aldioxa) Remainder 1000 mg A fine powder having the above composition was filled in an enteric capsule to prepare a capsule preparation for oral administration.

Powder composition 2: PTH (1-34) composition A PTH (1-34) composition is produced according to the following composition. PTH (1-34) 1962 μg Calcium stearate 60 mg Sofalcon (or sucralfate ) Remainder 1000 mg A fine powder having the above composition was filled in an enteric capsule to prepare an oral administration capsule preparation.

Powder composition 3: Buserelin composition A buserelin composition is produced according to the following composition. Buserelin 10,000 μg Calcium stearate 60 mg Sucralfate (or ardioxa ) Remainder 1000 mg A fine powder having the above composition was filled into an enteric capsule to prepare an oral administration capsule preparation.

The test examples and preparation examples described above are examples based on one embodiment in which a physiologically active peptide is used as a physiologically active substance and a gastric mucosal tissue repair / protective substance is selected as a carrier. Other physiologically active substances with low absorption due to administration, including other vitamins, antiallergic agents, immunosuppressants, parenteral antibiotics, parenteral antibacterial agents, osteoporosis therapeutic agents, etc. It goes without saying that the same applies to the case where a gastrointestinal intestinal substance such as domperidone, trimebutine maleate, cisapride, an HT ₃ -antagonist, or an HT ₄ -agonist is used as a carrier.

[0046]

As described above, according to the present invention, a physiologically active substance having a low absorbability by oral administration has been described.
By using a specific pharmaceutical carrier, a pharmaceutical composition for oral absorption having high bioavailability and high bioavailability is provided. In particular, the present invention comprises a physiologically active peptide such as calcitonin or insulin dispersed uniformly in a gastric mucosal tissue repair / protective substance or a gastrointestinal function regulating substance, which has not been considered as a pharmaceutical carrier for a physiologically active peptide. By orally administering the powder composition of the present invention as an enteric preparation, the stability of the peptide contained in the composition is excellent, the bioabsorbability is good, and effective clinical treatment is possible. Is suggested. Therefore, its medical effects are enormous.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 38/04 A61K 37/36 ABC 47/00 37/43

Claims (13)

[Claims] 1. A pharmaceutical composition for oral administration in which an effective dose of a physiologically active substance having low absorbability by oral administration is uniformly dispersed together with a substance for repairing / protecting gastric mucosal tissue or a substance for regulating gastrointestinal function. 2. A physiologically active substance having a low absorbability by oral administration includes a physiologically active peptide, various vitamins, an antiallergic agent, an immunosuppressant, a parenterally administered antibiotic, a parenterally administered antibacterial, and an osteoporosis treating agent. The pharmaceutical composition for oral administration according to claim 1, which is for example. 3. A gastric mucosal tissue repair / protective substance, wherein gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofalcone, teprenone,
Pranotol, rebamipide, aldioxa, cetraxate, troxipide, benexate hydrochloride betadex, a thiamine / cobalt / chlorophyllin complex compound, and the gastrointestinal function regulating substance is domperidone, trimebutine maleate, cisapride, an HT ₃ -antagonist, H
T ₄ - pharmaceutical compositions for oral administration according to claim 1, wherein the agonist. 4. An absorbability by oral administration selected from a physiologically active peptide, various vitamins, an antiallergic agent, an immunosuppressant, a parenterally administered antibiotic, a parenterally administered antibacterial agent, and a therapeutic agent for osteoporosis. Effective dosages of low bioactive substances include gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofacolcon, teprenone, praunotor, rebamipide, aldioxa, cetraxate, troxipide, venexate hydrochloride betadex, thiamine cobalt chlorophyllin Uniformly dispersed with at least one gastric mucosal tissue repair / protective substance selected from complex compounds or at least one gastrointestinal function regulating substance selected from domperidone, trimebutine maleate, cisapride, HT ₃ -antagonist, HT ₄ -agonist Sutra Pharmaceutical compositions for oral administration. 5. A pharmaceutical composition for oral administration in which an effective dose of a physiologically active peptide is uniformly dispersed together with a substance for repairing / protecting gastric mucosal tissue or a substance for regulating gastrointestinal function. 6. The pharmaceutical composition for oral administration according to claim 5, wherein the bioactive peptide is a peptide hormone, a bioactive protein, an enzyme protein, or an opioid peptide. 7. The peptide hormone may be calcitonin, insulin, thyroid stimulating hormone releasing hormone (TR).
H), luteinizing hormone-releasing hormone (LH-RH), L
H-RH antagonists, adrenocorticotropic hormone (AC
TH), corticotropin-releasing hormone (CR)
H), growth hormone releasing hormone (GH-RH), gonadotropin (gonadotropin), gonadotropin releasing hormone (GnRH), parathyroid hormone (PTH),
Growth hormone (GH), somatropin, prolactin (mammary stimulating hormone), follicle stimulating hormone (FSH),
The pharmaceutical composition for oral administration according to claim 5 or 6, which is glucagon, vasopressin, or somatostatin (a growth hormone release inhibitory factor). 8. The pharmaceutical composition for oral administration according to claim 5, which is in the form of an enteric preparation. 9. Calcitonin, insulin, thyrotropin releasing hormone (TRH), luteinizing hormone releasing hormone (LH-RH), LH-RH antagonist, adrenocorticotropin (ACTH), adrenocorticotropin releasing hormone (CRH) ), Growth hormone releasing hormone (GH-RH), gonadotropin (gonadotropin), gonadotropin releasing hormone (GnRH), parathyroid hormone (PTH), growth hormone (GH), somatropin, prolactin (mammary stimulating hormone), Follicle stimulating hormone (FSH), glucagon, vasopressin,
Effective doses of peptide hormones selected from somatostatin (growth hormone release inhibitory factor), gefarnate, aceglutamide aluminum, sucralfate,
L-glutamine, sofalcone, teprenone, praunitol, rebamipide, aldioxa, cetraxate,
Troxipide, benexate hydrochloride betadex, a gastric mucosal tissue repair / protective agent selected from thiamine / cobalt / chlorophyllin complex compound, or domperidone,
A pharmaceutical composition for oral administration which is uniformly dispersed with at least one gastrointestinal function regulating substance selected from trimebutine maleate, cisapride, an HT ₃ -antagonist and an HT ₄ -agonist, and is an enteric preparation. 10. A compound selected from gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofalcone, teprenone, praunitol, rebamipide, aldioxa, setraxate, troxipide, benexate hydrochloride betadex, thiamine-cobalt-chlorophyllin complex compound. Of a gastrointestinal function repairing / protecting agent or at least one gastrointestinal function regulating substance selected from domperidone, trimebutine maleate, cisapride, HT ₃ -antagonist and HT ₄ -agonist Agent. 11. Sofalcon which is a gastric mucosa tissue repair / protective substance as a stabilizing agent for a physiologically active peptide. 12. Sofalcon which is a gastric mucosal tissue repair / protective substance as an insulin stabilizing agent. 13. Sucralfate which is a gastric mucosal tissue repair / protective substance as a stabilizing agent for a water-soluble organizing active peptide.