KR20070031425A - PTH-Containing Preparation for Transmucosal Administration - Google Patents

Abstract

Providing the pharmaceutical composition obtained by suppressing the symptoms, such as nausea at the time of PTH administration. Administering to increase bone mass or bone density, and to inhibit an increase in the risk of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, wherein the pharmaceutical composition maintains both bone formation and bone resorption inhibitory effects of PTH.

Pharmaceutical composition for transmucosal administration, hPTH

Description

Transmucosal administration containing PTH {PTH-Containing Preparation for Transmucosal Administration}

The present invention relates to a pharmaceutical composition for transmucosal administration containing human parathyroid hormone (hPTH) or hPTH derivatives as an active ingredient. More specifically, the present invention relates to a pharmaceutical composition that suppresses symptoms such as nausea when hPTH is administered.

Parathyroid hormone (PTH) is known as one of the important hormones in bone metabolism, and the action of PTH on bone has been reported in the past.

Osteoporosis is a condition in which bone mass decreases and the microstructure of bone tissue changes, thereby causing bone to soften and fracture easily. Fractures of the spine, femoral neck, and radial end associated with osteoporosis have been reported to be associated with a decrease in QOL, and in particular, femoral bones do not occur in the pathology. Thus, countermeasures against osteoporosis are expected.

There are various causes involved in the occurrence of fractures, but among them, low bone density (bone mass) is evaluated as a major factor. Therefore, the significance of pharmacotherapy for osteoporosis is to prevent the reduction of bone mass and increase the bone mass, to prevent the occurrence of new fractures for patients at high risk of declining bone mass and increasing the possibility of fracture.

Current osteoporosis therapeutics include estrogen preparations, calcitonin formulations, active vitamin D preparations, ipriflavone formulations, vitamin K preparations, bisphosphonate formulations, calcium preparations and the like. However, most of these drugs are bone resorption inhibitors that suppress bone resorption by facilitating bone resorption and have an effect of increasing bone mass, and are not bone formation promoters that actively increase bone mass by acting on bone formation.

Human parathyroid hormone (hPTH) consists of 84 amino acid sequences and is a calcium regulatory hormone secreted from the parathyroid gland in response to calcium concentrations in the blood. It has been reported that the body of physiological activity of hPTH is in 34 fragments (PTH1-34) from the N terminus involved in binding to the receptor.

In addition, basic and clinical trials have reported the effect of hPTH on bone, which promotes bone resorption during continuous administration and promotes bone formation during intermittent administration. As such, since hPTH is considered to be a drug having an action mechanism different from that of the conventional osteoporosis therapeutic drug, it is expected as a new mechanism of osteoporosis therapeutic drug.

However, when hPTH was administered to a patient, observation of symptoms such as nausea (vomiting, nausea, gastric distress, etc.), leg cramps, headache, and dizziness was reported at a constant rate (Non-Patent Documents 1 and 2). See). In order to prevent these symptoms, it is good to reduce the amount of hPTH administered to the patient, but in such a case, the bone-boosting effect of hPTH, which is originally intended, will be lost.

In order to reduce the symptoms upon administration of hPTH, a combination of anti-emetic drugs such as teprenone has been reported (see Patent Document 1), but the electric method only reduces nausea, vomiting and stomach discomfort among various symptoms, The drawback is that there is an increase in administration of the drug by one.

In addition, although it was reported about the transnasal pharmaceutical composition containing hPTH (refer patent document 2-4), the relationship with the electrical symptom was not reported at all.

Therefore, a method of administering hPTH that suppresses symptoms such as nausea, leg cramps, and headache dizziness is expected while maintaining the bone mass increasing effect of hPTH.

Patent Document 1: Japanese Patent Application Laid-Open No. 2003-95974

Patent Document 2: Japanese Patent Application Laid-Open No. 61-282320

Patent document 3: Unexamined-Japanese-Patent No. 4-247034

Patent Document 4: WO 02/021136 International Publication Pamphlet

[Non-Patent Document 1] Neer et al., N. Eng. J. Med. 344, 1434-1441, (2001)

[Non-Patent Document 2] Fujita et al., Osteoporsis Int. 9. 296-306, (1999)

Disclosure of the Invention

Challenges the invention seeks to solve

An object of the present invention is to provide a method for inhibiting the symptoms such as nausea when administering PTH described above, and a pharmaceutical composition for suppressing it.

Means to solve the problem

The inventors of the present invention have symptoms such as nausea, leg cramps, headache, and dizziness when hPTH is administered subcutaneously, but when it is not administered, the symptoms do not appear or their symptoms are maintained while maintaining the action of hPTH. The rate of onset was found to be lowered.

Therefore, in order to prevent symptoms such as nausea, leg cramps, headache, and dizziness, it is preferable to administer hPTH by transmucosal membranes such as nasal passages while maintaining hPTH's bone mass increasing effect.

That is, this invention is as mentioned later.

[1] A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[2] The pharmaceutical composition for transmucosal administration of [1], which is a bone mass increasing agent.

[3] The pharmaceutical composition for transmucosal administration of [1], which is a bone density increasing agent.

[4] The pharmaceutical composition for transmucosal administration of [1], which is a therapeutic agent for osteoporosis.

[5] The pharmaceutical composition for transmucosal administration of [1], which is a bone resorption inhibitor.

[6] The pharmaceutical composition according to any one of [1] to [5], which promotes bone formation and suppresses bone resorption.

[7] The pharmaceutical composition of any one of [1] to [6], which is a transnasal administration agent.

[8] The pharmaceutical composition of any one of [1] to [7], wherein hPTH is hPTH1-34.

[9] The pharmaceutical composition according to any one of [1] to [8], wherein the daily dose is 250 µg to 1000 µg.

[10] The pharmaceutical composition of any one of [1] to [8], wherein the pharmaceutical composition is formulated so that a single dose is 250 µg to 1000 µg.

[11] inhibiting increasing bone mass or bone density and increasing the risk of developing one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, which is administered for the purpose.

[12] administered to increase bone mass or bone mineral density, and to inhibit an increase in the probability of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[13] administered for the purpose of increasing bone mass or bone density, and inhibiting the increased incidence of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[14] administered to lower the risk of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration, while maintaining hPTH-increasing or increasing bone mineral density A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[15] Administered to lower the probability of onset of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration, while maintaining hPTH-increasing or increasing bone mineral density A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[16] administered to reduce the incidence of at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration while maintaining bone mass gain or bone mineral density increase of hPTH A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof.

[17] A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, which is administered for the purpose of maintaining both bone formation and bone resorption inhibitory effects of hPTH.

[18] The pharmaceutical composition of any of [11] to [17], wherein the transmucosal membrane is a nasal mucosa.

[19] The pharmaceutical composition of any of [11] to [18], wherein hPTH is hPTH1-34.

[20] The pharmaceutical composition of any of [11] to [19], wherein the daily dosage is 250 µg to 1000 µg.

[21] The pharmaceutical composition of any of [11] to [19], wherein the pharmaceutical composition is formulated so that a single dose is 250 µg to 1000 µg.

[22] A method of administering hPTH or a derivative thereof in the transmucosal membrane to reduce the risk of developing one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration.

[23] A method of administering hPTH or a derivative thereof in the transmucosal membrane to reduce the probability of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration.

[24] A method of administering hPTH or a derivative thereof in the transmucosal membrane to reduce the incidence of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration.

[25] The method of any of [22] to [24], wherein the action of increasing bone mass or increasing bone density of hPTH is maintained.

[26] A method of administering hPTH or a derivative thereof in the transmucosal membrane to maintain both bone formation and bone resorption.

[27] The method of any of [22] to [26], wherein the transmucosal membrane is a nasal mucosa.

[28] A method of maintaining bone repression inhibition by administering hPTH or a derivative thereof by a method of short half-life in blood compared to subcutaneous administration.

[29] A method of administering hPTH or a derivative thereof by a method of shorter half-life in blood as compared with subcutaneous administration to maintain bone formation and bone resorption.

[30] The method of any of [22] to [29], wherein hPTH is hPTH1-34.

[31] The method of any of [22] to [30], wherein the daily dose is 250 µg to 1000 µg.

To practice the invention  for Best  shape

Hereinafter, the present invention will be described in detail.

As described above, administration of hPTH may increase the risk of developing symptoms such as nausea, leg cramps, headache, and dizziness, and increase the likelihood of developing or developing an electrical symptom compared to the case of no administration of hPTH. Yes has been reported.

The pharmaceutical composition for transmucosal administration comprising hPTH of the present invention as an active ingredient lowers the onset of symptoms of symptoms such as nausea, leg cramps, headaches, and dizziness, while maintaining the action of hPTH, or increases the incidence of electrical symptoms. Reported.

The maintenance of the action is not limited to the extent of the action, and the action may be observed, but it is preferable that the action is maintained to a degree that is recognized as therapeutically effective (eg, therapeutically effective for osteoporosis).

In describing the present invention, the "action of hPTH" (action of hPTH) refers to the action of increasing bone mass, increasing bone density, inhibiting bone resorption, and the like. When hPTH maintains these effects, it can be used for the purpose of the treatment of osteoporosis, the prevention of a fracture, etc. In the present invention, the maintenance of the action of hPTH means that when the hPTH is administered, the action of hPTH is observed in the administered patient. The bone mass increasing effect, the bone density increasing effect, and the bone resorption inhibitory effect can be measured by a method known to those skilled in the art, for example, by the method described in Examples.

In describing the present invention, "inhibiting an increase of a risk of developing symptoms" means inhibiting an increase in the risk of developing unintended symptoms according to the administration of hPTH. do. In addition, "to inhibit an increase" means to extinguish the increase itself or to reduce the extent of the increase. "Risk of developing symptoms" means the administration of hPTH. It means the risks that come from unintended symptoms. In the present invention, when hPTH is administered by a route of administration other than transmucosal administration (subcutaneous administration, etc.), when the risk of unintentional development of symptoms is reduced, the risk of development is suppressed (a risk of developing symptoms is reduced).

It has been found by the present invention that the risk of developing unintended symptoms when the hPTH is administered by a route of administration other than transmucosal administration (subcutaneous administration, etc.) can be inhibited by transmucosal administration.

In describing the present invention, "to reduce a frequency of developing symptoms" means reducing the proportion of patients who develop unintended symptoms in the patient group administered hPTH. Therefore, the onset frequency refers to the proportion of patients in whom symptoms develop among the group of patients to which hPTH was administered. For example, in 100 patients with hPTH administration, when a symptom is observed in 10 patients, the frequency of onset of the symptom becomes 10%. In this case, the frequency of onset is referred to as "reducing the frequency of symptoms." It means to be less than 10% (the number of patients where symptom is observed 9 or less).

The determination of whether or not the onset frequency is decreasing is performed based on the frequency of onset of symptoms when hPTH is administered by a route of administration other than transmucosal administration (especially nasal administration) (eg, subcutaneous administration).

More specifically, subcutaneous administration of hPTH1-34 has been reported with 13% of headaches, 18% of nausea, 9% of dizziness, and 3% of leg cramps (see Robert M Neer et al.). , N Engl J Med, 344 (19), 1434-1441, (2001). Accordingly, in the present invention, in the preferred embodiment of "decreasing the onset of symptoms", when the symptoms are headaches, the incidence is less than 13%, preferably less than 10%, more preferably less than 9%. In case of nausea, the incidence is less than 18%, preferably less than 10%, more preferably less than 5% .In case of symptomatic dizziness, the incidence is less than 9%, preferably less than 7%. Preferably it is less than 6%, and if symptoms are leg cramps, the frequency of onset is less than 3%, preferably less than 2%, more preferably less than 1%.

For example, in the case of nasal administration, the onset of symptoms is 7.2%, nausea 0%, immobility dizziness 4.1%, leg cramps 0%, which is significantly lower than in subcutaneous administration. It can lower your risk.

In describing the present invention, "to reduce a probability of developing a symptom" means reducing the probability of developing an unintended symptom in a particular patient. Thus, in the case of `` reducing a frequency of developing a symptom, '' the subject may be a group (patient), but `` reducing a probability of developing a ''. In the case of symptoms, the subject is a specific patient. Therefore, "the probability of developing a symptom" means the probability that a particular patient will develop symptoms when hPTH is administered to a particular patient. Normally, whether or not the probability of developing a symptom is reduced is the same as in the case of reducing a probability of developing a symptom. It can be judged from the proportion of patients with symptomatic expression among the group of patients who were administered A. In addition, whether or not the probability of onset of symptoms is decreasing is based on the probability of onset of a particular symptom in a group in which hPTH was administered by a route of administration other than transmucosal administration (especially nasal administration) (eg, subcutaneous administration). Is performed. In the present invention, the number of populations (patients) is not limited, but is usually 5 or more, preferably 15 or more, more preferably 20 or more, and particularly preferably 25 or more.

As described above, when the pharmaceutical composition of the present invention is administered by transmucosal membranes, the probability of onset of symptoms and the frequency of onset of symptoms are lowered compared to those administered by administration routes other than transmucosal membranes. For example, one or more symptoms selected from leg cramps, nausea, headache and dizziness dizziness are lost, or the probability of symptoms developing and the incidence of symptoms decrease by almost one half.

In the present invention, an unintended symptom that decreases the probability of onset or decreases the frequency of onset is preferably indicated by a high frequency by administering hPTH by administration route other than transmucosal administration (for example, subcutaneous administration). Symptoms that are not, including leg cramps, nausea (nausea, vomiting, stomach discomfort, etc.), headaches, and dizziness.

In addition, by administering hPTH by transmucosal administration such as nasal administration, it is possible to reduce the onset of the above-mentioned undesirable symptoms while maintaining hPTH's bone mass increasing effect, bone density increasing effect or bone resorption effect.

In addition, when hPTH is administered in general, when bone resorption is inhibited, bone formation is also inhibited, and both bone repression inhibitory effect and bone formation action of hPTH cannot be maintained.

However, in the present invention, it was found that by administering hPTH by a short administration method, blood half-life in blood can maintain both bone formation and bone resorption inhibitory effects of hPTH.

In the present invention, a shorter half-life of the administration method means a shorter half-life of the administration compared to subcutaneous injection. Specific administration methods with short blood half-lives include transmucosal administration (eg, nasal administration), vascular administration (eg, intravenous administration), and the like.

The half-life in blood at the time of administration of hPTH can be measured by a method known to those skilled in the art, for example, the half-life in blood can be measured by the method described in the Examples.

As a result, the present invention relates to a method for maintaining bone resorption inhibitory activity by administering hPTH or a derivative thereof by short administration method of blood half-life, in particular, a method for maintaining both bone resorption inhibitory activity and bone formation.

As a preferable aspect of this invention, the method of administering hPTH or its derivative (s) to a transmucosal membrane and maintaining both a bone formation effect and a bone resorption inhibitory effect is mentioned.

The hPTH used in the present invention may be any hPTH, and includes full-length hPTH, hPTH derivatives, modified hPTH, and the like. Also included are native PTH, recombinant PTH prepared by genetic engineering methods, and chemically synthesized PTH.

Examples of hPTH derivatives include hPTH (1-84) (Biochemistry 17,5723 (1978), Kimura et al., Biochem. Biophys.Res.Commun., vol.114, p493, 1983), hPTH (1-38) ( Reference: Japanese Patent Application Laid-Open No. 57-81448, hPTH (1-34) (see Japanese Patent Application Laid-Open No. 9-29600, Takai et al., Peptide Chemistry, 1979, p187), hPTH (1-34) NH ₂ (reference: Patent Publication No. 58-96052 ^{points), [Nle 8, 18]} hPTH (1-34), [Nle 8, 18, Tyr 34] hPTH (1-34) ( reference: Patent Publication No. 55-113753 arc portion), [ ^{Nle 8, 18] hPTH (1-34} ) NH 2 ( reference: Patent Publication No. 61-24598 ^{points), [Nle 8, 18,} Tyr 34] hPTH (1-34) NH 2 ( see: Patent 60-34996 portion Call), hPTH (1-34) (see Japanese Patent Application Laid-Open No. Hei 5-505594), hPTH (2-84), hPTH (3-84), hPTH (4-84), hPTH (5-84), hPTH (6-84), hPTH (7-84), hPTH (8-84) (see Japanese Patent Application Laid-Open No. 4-505259) and the like. In addition, in the above-mentioned hPTH, a component amino acid is partially substituted with another amino acid, a part of the structural amino acid is deleted, and one or more amino acids are added to the structural amino acid, and those having the same activity are also included. Preferred examples of amino acid substitution are substitution of leucine or norleucine of the constituent amino acid at position 8, substitution of leucine or norleucine of constituent amino acid at position 18, position 34 In the above examples, substitution of tyrosine with a constituent amino acid is given.

Preferred hPTH in the present invention is hPTH (1-34).

hPTH can be produced by a method known to those skilled in the art, and can be produced by, for example, a method by genetic engineering technique, chemical synthesis technique, or the like (see Japanese Patent Laid-Open No. Hei 9-296000, Japanese Patent Application Laid-Open). 2643968, etc.). The prepared hPTH can be purified using a method such as known column chromatography. hPTH is a basic peptide, and an acid such as acetic acid can be used as the eluent in order to avoid adsorption to a column resin. When an acid is used in the purification, it is preferable to reduce the amount of the electric acid in the pharmaceutical composition containing hPTH. The acid can be reduced by known methods such as dialysis, electrodialysis, ion exchange chromatography, gel filtration, reverse phase HPLC and the like.

Since the pharmaceutical composition for transmucosal administration containing the hPTH of the present invention as an active ingredient has a good blending property, it is a carrier, excipient, thickener, preserver, stabilizer, and antioxidant commonly used after formulation. , Binders, disintegrants, wetting agents, lubricants, colorants, fragrances, corrigents, suspending agents, emulsifiers, dissolution aids, buffers, isotonic agents, surfactants, soothing agents, sulfur-containing reducing agents In addition to ingredients such as sulfur-containing reducing agents, various other functional ingredients may be suitably blended for the purpose of improving absorption and stabilizing solids.

Examples of the carrier or excipient are water-soluble or sparingly soluble, and include sugars, polysaccharides, dextrins, celluloses, synthetic or semisynthetic polymers, amino acids, polyamino acids, proteins, phospholipids, and the like. have.

Examples of the sugars (monosaccharides and small sugars) include D-mannitol, glucose, lactose, fructose, inositol, sucrose and maltose, and the polysaccharides include dextran, pullulan, Alginic acid (alginic acid), hyaluronic acid (hyaluronic acid), pectic acid (pectic acid), phytic acid (phytic acid), phytin and the like. Examples of dextrins include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dextrin, hydroxypropyl starch, hydroxyethyl starch and the like.

Examples of the celluloses include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium and the like.

Examples of the synthetic and semisynthetic polymers include polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, sodium polyacrylate, polylactic acid and the like.

Examples of the amino acids include glycine, taurine, and the like, and examples of the polyamino acids include polyglutamic acid, polyaspartic acid, polyglycine, and polyleucine.

Examples of proteins include gelatin and the like. In addition, chitin, chitosan, etc. are mentioned.

Among these carriers or excipients, in particular, sucrose, maltose, α-cyclodextrin, β-cyclodextrin, dextrin, D-mannitol, inositol, lactose, dextran, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, flulan desirable.

In addition, sorbic acid, benzalconium chloride, cetylpyridinium chloride, benzethonium chloride, or methyl para-hydroxybenzoate, ethyl paraoxybenzoate parabens such as para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate, and isobutyl para-hydroxybenzoate, gum arabic, consumption Sorbitol, magnesium stearate, talc, silica, crystalline cellulose, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium lauryl sulfate, water, ethanol, glycerin You can also use syrup.

As surfactant, nonionic surfactant, for example, sorbitan fatty acid ester, such as sorbitan monocaprilate, sorbitan monolaulate, sorbitan monopalmitate, etc. ; Glycerin fatty acid esters such as glycerin monocaprylate, glycerin monomyristate, and glycerin monostearate; Polyglycerol fatty acid esters such as decaglyceryl monostearate, decaglyceryl distearate and decaglyceryl monolinoleate; Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan tree Polyoxyethylene sorbitan fatty acid esters such as oleate and polyoxyethylene sorbitan tristearate; Polyoxyethylene sorbitol fatty acid esters such as polyoxyethylene sorbitol tetrastearate and polyoxyethylene sorbitol tetraoleate; Polyoxyethylene glyceryl fatty acid esters such as polyoxyethylene glyceryl monostearate; Polyethylene glycol fatty acid esters such as polyethylene glycol distearate; Polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; Polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether; Polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether; Polyoxyethylene hardened castor oil, such as polyoxyethylene castor oil and polyoxyethylene hardened castor oil (polyoxyethylene hydrogen castor oil); Polyoxyethylene beeswax derivatives such as polyoxyethylene sorbitol beeswax; Polyoxyethylene lanolin derivatives such as polyoxyethylene lanolin; Those having HLB 6 to 18 such as polyoxyethylene fatty acid amide such as polyoxyethylene stearic acid amide; Anionic surfactants such as alkyl sulfates having 10 to 18 carbon atoms, such as cetyl sulfate, sodium lauryl sulfate, and oleyl sulfate; Polyoxyethylene alkyl ether sulfates having an average added mole number of ethylene oxide, such as polyoxyethylene lauryl sulfate, of 2 to 4 and 10 to 18 carbon atoms in the alkyl group; Alkyl sulfo succinic acid ester salt having 8 to 18 carbon atoms in an alkyl group such as sodium lauryl sulfo succinic acid; Natural surfactants such as lecithin, glycerophospholipids; Spingolipids such as spingomyelin; Sucrose fatty acid esters of fatty acids having 12 to 18 carbon atoms are exemplified. To the formulation of the present invention, one or two or more of these surfactants may be added in combination. Sulfur-containing reducing agents include N-acetyl cysteine, N-acetyl homocysteine, thioctic acid, thiodiglycol, thioethanolamine and thioglycerol , Sulfhydryl groups such as thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, glutathione, and thialkanic acid having 1 to 7 carbon atoms For example, having a.

Further, antioxidants include erysorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L- Ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, triamyl gallate, acetic acid propyl or ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, sodium methacrylate Chelating agents, such as these, are mentioned.

In the pharmaceutical composition of the present invention, the ratio of each component is about 0.01 to 20% of hPTH, preferably about 0.05 to 10%, and an organic acid may be added as necessary, and when used, about 0.05 to 99.5%, preferably It is about 0.1-99.0%, and components, such as a carrier or excipient normally used in formulation, can be added as needed, and when used, 0.01-99.5% is added, for example. In addition, various other functional ingredients may be added as necessary, and, for use, for example, about 0.05 to 99.5% is added.

The pharmaceutical composition containing the hPTH of this invention as an active ingredient can be administered by transmucosal administration. Transmucosal administration may be any form of administration via mucosal administration such as nasal administration, transpulmonary administration, transrectal administration, sublingual administration, oral oral administration.

Preferred transmucosal administration in the present invention is nasal administration.

The formulation for nasal administration is not particularly limited and may be any formulation such as droplets, sprays, mists, coatings, powders, gels, and the like. It is absorbed by tissues and / or vascular in the nose and / or sinus tract.

Non-administrative pharmaceutical compositions of hPTH can be prepared by known methods (see WO 02/02136, etc.).

The pharmaceutical composition for nasal administration of the present invention can be prepared according to a known method.

For example, a pharmaceutical component of hPTH having reduced acetic acid may be used as a pharmaceutical composition, and components such as carriers or excipients commonly used in the formulation of the pharmaceutical component of hPTH having reduced acetic acid as needed, and an organic acid. Alternatively, various functional ingredients may be added and combined to be used as a pharmaceutical ingredient. The compounding may be carried out by addition other than the substitution of the organic acid to acetic acid, for example, a mixture composed of organic acids or various functional components such as carriers or excipients which are commonly used in formulating as necessary for the pharmaceutical component of hPTH. May be dissolved in distilled water once and lyophilized to obtain a uniform composition.

In addition, the pharmaceutical components of hPTH and components such as carriers or excipients which are commonly used in formulating as needed, are dissolved in distilled water once and lyophilized, and then organic acids or various functional components are collected, dissolved and lyophilized as necessary. It is also possible to obtain a uniform composition.

Alternatively, a pharmaceutical composition of hPTH, an organic acid or various functional components are dissolved in distilled water once and lyophilized, and then, as necessary, components such as a carrier or an excipient commonly used in formulation are collected, dissolved, and lyophilized to obtain a uniform composition. May be obtained.

The pharmaceutical component of the present invention can be formulated into various formulations by a method of administration, and can be formulated into formulations capable of mucosal administration such as rectal, nasal, oral cavity. In addition, the pharmaceutical composition for nasal administration of the present invention is preferably administered in the form of a nasal agent.

Preferred examples of the non-administration pharmaceutical composition of the present invention, the soluble component of the present invention, which is provided as a lyophilized composition, is contained in a lyophilized portion, and a dissolving type in which a dissolving solution portion is attached thereto. A formulation dissolved before use is an example.

Organic acids such as citric acid, adipic acid and glycolic acid as the above-mentioned organic acid and absorption promoter may be dissolved or added to the medicinal component of the present invention as a salt or an attachment or an additive with hPTH in the freeze-dried portion. .

In addition, the administration of the non-administration pharmaceutical composition of the present invention can be carried out according to a known method, for example, the pharmaceutical composition for administration of the non-administration of the present invention is a formulation used as a nasal agent, for example, containing an electric pharmaceutical composition The intranasal administration method by spraying which sprays a sprayer to a container and puts the tip of a nozzle in a nasal cavity and sprays can be applied.

The dosage of the pharmaceutical composition of the present invention also varies depending on the type of disease, the age, weight of the patient, the severity of the symptoms, and the route of administration. Or divided into several times can be administered per day, it can be administered in the range of 10 μg to 5000 μg, preferably in the range of 250 μg to 1000 μg as hPTH (1-34) per time. In addition, once a drug is suspended, it may be administered again depending on the symptoms.

In addition, the dosage per day is not particularly limited and can be appropriately determined by those skilled in the art, but is, for example, 250 μg to 1000 μg in the amount of hPTH or a derivative thereof. In order to perform such administration, for example, the pharmaceutical composition of the present invention may be adjusted with a pharmaceutical preparation so that the dosage is 250 µg to 1000 µg, and the administration may be performed once a day.

This specification includes part or all of the contents as disclosed in the description and / or drawings of Japanese Patent Application No. 2004-207733, which is a priority document of the present application.

1 is a graph showing the rate of change in bone density after 12 weeks of administration of the pharmaceutical composition of the present invention.

Figure 2a is a graph showing the rate of change 6 weeks after administration of blood PINP, a bone formation marker.

Figure 2b is a graph showing the rate of change 12 weeks after administration of blood PINP, a bone formation marker.

Figure 3a is a graph showing the rate of change 6 weeks after administration of NTx in urine, a bone resorption marker.

3B is a graph showing the rate of change after 12 weeks of administration of urinary NTx, a bone resorption marker.

Figure 4 is a graph showing the lumbar spine (lumbar vertebra) bone density increase in the aged OVX rat of hPTH (1-34).

Figure 5 is a graph showing the effect on bone resorption markers in old OVX rats of hPTH (1-34).

Figure 6 is a graph showing the effect on bone formation markers in OVX rats of hPTH (1-34).

Figure 7a is a graph showing the blood concentration trend of hPTH (1-34) through iv administration in rats.

Figure 7b is a graph showing the plasma concentration of hPTH (1-34) through the administration of sc in rats.

8 is a graph showing the lumbar spine bone mineral density increase effect in the elderly OVX rat of hPTH (1-34).

9A is a graph showing the effect on bone resorption markers (DPD / Cre) in old OVX rats of hPTH (1-34).

9B is a graph showing the effect on bone resorption markers (TRACP5b) in old OVX rats of hPTH (1-34).

FIG. 10 is a graph showing the effects on bone formation markers (osteocalcin) in old OVX rats of hPTH (1-34).

FIG. 11A is a graph showing the effect on bone mass parameters (BV / TV) of PTH (1-34) in old OVX rats.

FIG. 11B is a graph showing the effect on the bone mass parameter (Tb.Th) of PTH (1-34) in old OVX rats.

12A is a graph showing the effect on bone resorption parameters (ES / BS) of PTH (1-34) in old OVX rats.

12B is a graph showing the effect on bone resorption parameters (N.Oc / BS) of PTH (1-34) in old OVX rats.

FIG. 13A is a graph showing the effect of PTH (1-34) on bone formation parameters (BFR / BS) in old OVX rats.

FIG. 13B is a graph showing the effect of PTH (1-34) on bone formation parameters (LS / BS) in old OVX rats.

Although the present invention has been described in detail by the following examples, the present invention is not limited to these examples.

Example 1 Effect on Patients with Primary Osteoporosis

The effect of the pharmaceutical composition of this invention was investigated by the following method.

Subject: Primary osteoporosis patient

Design: Comparison of among randomly allotted parallel groups

Usage and dose: 250 μg, 500 μg, or 1000 μg of hPTH (1-34) was administered daily daily.

Specifically, when lyophilized composition comprising hPTH (1-34) prepared to contain 250 μg, 500 μg, or 1000 μg of hPTH (1-34) in 200 μl of the drug solution when dissolved in the solution It was used by dissolving. In addition, the hPTH1-34 nonadministration agent was prepared by the method of Formulation Example 2 of WO 02/02136. A total of 200 µl was sprayed into the nasal cavity once daily by using a sprayer VP-7 (manufactured by Valois), which was pumped once and 100 µl was uniformly sprayed.

Test Methods: Patients with primary osteoporosis were randomly assigned to three groups of 250 µg, 500 µg and 1000 µg. HPTH (1-34) of each dose was sprayed once a day for 12 weeks, confirming the effectiveness and stability of each dose.

Evaluation of efficacy: The rate of change of BMD up to 12 weeks, the rate of change of blood PINP, a bone formation marker, and the rate of change of blood NTx, a bone resorption marker, were evaluated.

Specifically, the rate of change of the second to fourth lumbar spine BMD (L2-4BMD) after 12 weeks of administration measured by the DXA method, the rate of change of the blood PINP which is a bone formation marker measured by the RIA method, and the ELISA method The rate of change of urinary NTx, a bone resorption marker, was evaluated. In addition, measuring the measurement of the UniQ PINP RIA (Orion Diagnostica Co.) _X NT of PINP was used for austenite O mark (Osteomark) (mochida pharmaceutical agent).

Evaluation of safety: The number of expression examples of adverse events was counted and evaluated, and the following results were obtained.

Bone density change (mean) at 12 weeks of administration increased dose-dependently with 0.14% in 250 µg, 0.69% in 500 µg group, 2.44% in 1000 µg group, and significantly increased at 1000 µg compared with the start of administration. . In addition, the 1000 ㎍ group showed a significantly higher increase rate compared to the 250 ㎍ group. Figure 1 shows the bone density change rate.

The change rate (median) at 6 weeks of administration of the blood formation marker PINP was 4.1% in the 250 µg group, 16.5% in the 500 µg group, and 24.3% in the 1000 µg group. Significant elevation was observed in the 500 μg group and the 1000 μg group compared to the start of administration. At 12 weeks of administration, the change rate was 1.4% in the 250 µg group, -0.84% in the 500 µg group, and 14.8% in the 1000 µg group. Significant elevations were observed in the 1000 μg group compared with the start of administration. 2 shows the rate of change of blood PINP.

The change rate (median) at 6 weeks of administration of urinary NTx, a bone resorption marker, was -3.0% in the 250 µg group, -22.2% in the 500 µg group, and -26.1% in the 1000 µg group, compared with the 250 µg group in the 500 µg group. The rate of decline was significant. Significant decreases were observed in the 500 μg group and the 1000 μg group compared to the start of administration. At 12 weeks of administration, the change rate was -8.7% in the 250 µg group, -28.6% in the 500 µg group, and -16.4% in the 1000 µg group. The 500 μg group had a significantly lower drop rate compared to the 250 μg group. Significant decreases were observed in the 500 μg group and the 1000 μg group compared to the start of administration. 3 shows the rate of change of urinary NTx.

In the aggregate of harmful thoughts, the name of the harmful thoughts was read as a basic language (PT) based on the MedDRA Version 6.1, and classified into SOCs.

Among 97 safety evaluation examples, 155 adverse events occurred in 70 cases (72.2%). The number of expressions per administration group was 46 in 22 cases (71.0%) in the 250 μg group, 51 cases in 23 cases (76.7%) in 30 cases in the 500 μg group, and 20 cases in 29 cases in the 1000 μg group ( 69.0%) and 10 cases were found in 5 cases (71.4%) among 7 cases in 1500㎍ group. Among them, 7% or more of nasopharyngitis (14.4%), 7 cases of headache (7.2%), 12 cases of supraventricular premature beat (12.4%). Ventricular premature beat was found in 5 cases (5.2%). In SOC, 21 patients (21.6%) had heart failure, 19 patients (19.6%) had clinical examination, and 18 patients (18.6%) with infectious diseases and parasites.

Subcutaneous administration has been reported with leg cramps (3%), nausea (18%), immobility dizziness (9%), and headaches (13%) (see Robert M Neer et al., N Engl Med). , 344 (19), 1434-1441, (2001)), and no spasticity and nausea were observed by nasal administration of the administration route, and the expression rate was markedly decreased in immobilized dizziness (4.1%) and headache (7.2%).

There were 37 adverse events in 24 cases (24.7%). The number of expressions per administration group was 12 in 7 cases (22.6%) in the 250μg group, 10 cases in 8 cases (26.7%) in the 30g 500g group, and 7 cases in 29 cases (24.1) in the 1000μg group. %) And 2 cases (28.6%) out of 7 cases in 1500g group. None of them had an expression rate of more than 5%.

From the results of efficacy and safety in this clinical examination, it was concluded that the agent had an effect of significantly increasing bone density by promoting bone formation and suppressing bone resorption, and was also an excellent drug for safety.

Example 2 Effect on Bone Metabolism by Administration of PTH (1-34) in Caudal Vein (iv) in Old Ovariectomized Rats

PTH (1-34) was administered intravenously (iv) in aged OVX rats, and the effects on bone metabolism were examined.

Bilateral ovarian extraction (OVX) and gastric surgery (sham) of 34-week-old female SD-IGS rats were performed. The bone density of the OVX group was measured at 48 weeks of age, and rats were divided so that the average BMD of each group was equal to 8 groups.

hPTH (1-34) was diluted with phosphate buffer (PBS) /0.05% Tween80 and hPTH (1-34) was prepared to be 10, 2.5, 0.625 nmol / ml. 1 ml / kg (10, 2.5, 0.625 nmol / kg) of phosphate buffer (PBS) /0.05% Tween80 in each of the sham and OVX groups, and diluted hPTH (1-34) in each of the 8 mice. 5 times a week for 6 weeks intravenously. Rats are placed in a metabolic cage on the last day of dosing, 24-hour urine is collected, blood is collected from the anesthesia under anesthesia the day after the last day of dosing, and the rats are euthanized. After necropsy, blood, lumbar spine and femur were obtained. Urine and blood were placed in a tube, the supernatant was obtained by centrifugation, and stored at a set temperature of −20 ° C. until parameter measurement. Lumbar and right femur were preserved in 70% ethanol. The mean bone density of the lumbar vertebrae (second to fifth lumbar vertebrae) and the bone mineral density of the right femur were measured using a dual X-ray bone salt measuring device (DCS-600EX, alloca). Serum and urine measured bone metabolism markers, the results are shown in Figure 4 results.

As shown in Figure 4, the OVX group showed a significant decrease in bone mineral density compared to the gastric surgery group in the lumbar spine. In addition, hPTH (1-34) showed significant and dose-dependent increase in bone density in the lumbar spine relative to the OVX group.

Then, deoxypyridinoline (DPD) in urine, a bone resorption marker, was measured, and the results are shown in FIG. 5. DPD was corrected with creatinine levels in urine. In urine DPD, a significant decrease of 0.625 nmol / kg of the iv-administered group of PTH (1-34) was observed, but no significant decrease was observed at doses of 2.5 and 10 nmol / kg.

Subsequently, osteocalcin (OC), a bone marker, was measured and the results are shown in FIG. 6. The OVX group was significantly increased for the sham group, and a significant increase was observed for the OVX group at doses of 2.5 and 10 nmol / kg of the PTH (1-34) group.

As described above, BMD increased in iv administration of PTH (1-34), while bone resorption markers decreased while bone formation markers increased. This suggests that iv administration of PTH (1-34) can inhibit bone resorption at low doses.

Example 3 Concentration of Plasma Concentrations in Intravenous and Subcutaneous Administration of PTH (1-34)

The plasma concentrations during intravenous (iv) and subcutaneous (sc) administration of hPTH (1-34) were examined. hPTH (1-34) was diluted with phosphate buffer (PBS) /0.05% Tween 80 and formulated to 10 nmol / ml. 8-week-old female SD-IGS rats were used for the experiment. Single iv and sc administrations were made and collected over time (pre, 2.5, 5, 7.5, 10, 15, 30, 60, 90, 120 minutes) from the vena cava using a capillary for blood collection. After EDTA plasma was isolated, it was stored at -80 ° C until the concentration of hPTH (1-34) was measured. PTH (1-34) concentration was measured by ELISA using PTH (1-34) (human) -EIA kit (Peninsula Laboratories). The concentration of PTH (1-34) in plasma and the pharmacokinetic parameters calculated therefrom are shown in FIGS. 7A and 7B and Table 1.

It was confirmed that iv administration of hPTH (1-34) showed more pulse-like PK compared to sc administration.

Pharmacokinetic Parameters of hPTH (1-34) Tmax (min) Cmax (ng / mL) T1 / 2 (min) AUC (ng / mL * min) iv - - 6.9 1066 sc 20 9.0 10.8 230

Example 4 Differences in Effects of Bone Metabolic Rotation in Intravenous and Subcutaneous Administration of PTH (1-34) in Old Ovarian Extracted Rats

In elderly OVX rats, intravenous (iv) and subcutaneous (sc) administration of PTH (1-34) was performed, and the difference in the effect of the difference in PK of PTH (1-34) on bone metabolism rotation was examined. It was.

hPTH (1-34) was dissolved in 10 mM acetic acid solution, and then dispensed in 10 nmol / mL using 25 mmol / L phosphate-citric acid buffer, 100 mmol / L NaCl, 0.05% Tween80 buffer (pH 5.0), and until use. It was preserved at 80 degrees.

Bilateral ovarian extraction (OVX) and gastric surgery (sham) were performed on 33-week-old female SD-IGS rats. After 28 weeks, bone density of OVX was measured, and rats were divided so that the average BMD of each group was equal to 8 groups.

Preserved hPTH (1-34) was diluted in phosphate-citric acid buffer, and hPTH (1-34) was prepared so that it might be set to 10, 2.5, 0.625 nmol / ml. The buffer solution was administered to each of the sham and OVX groups of 8 rats, and the diluted hPTH (1-34) was administered to each of the 8 rats at a dose of 1 ml / kg (10, 2.5, 0.625 nmol / kg) iv five times a week for 6 weeks. . In addition, group 1 sc administered 0.625nmol / ml of hPTH (1-34) at a dose of 1ml / kg (0.625nmol / kg) five times a week for 6 weeks. Rats were housed in metabolism cages on the last day of administration, urine was collected for 24 hours, blood was collected from the anesthesia of the lower abdominal aorta on the day after the last day of administration, and rats were euthanized and autopsied to obtain lumbar and femurs. Urine and blood were placed in a tube, the supernatant was obtained by centrifugation and stored at -20 ° C until the parameter measurement. Lumbar and right femur were preserved in 70% ethanol. The mean bone density of the lumbar vertebrae (second to fifth lumbar vertebrae) and the bone mineral density of the right femur were measured using a dual X-ray bone salt measuring device (DCS-600EX, alloca). In addition, the third lumbar spine performed bone morphology. Serum and urine measured bone metabolism markers, and the results are shown in FIG. 8.

As shown in Figure 8, the OVX group showed a significant decrease in bone mineral density compared to the gastric surgery group in the lumbar spine. In addition, hPTH (1-34), the iv administration group showed a significant and dose-dependent increase in bone density in the lumbar spine relative to the OVX group. In addition, the sc-administered group of hPTH (1-34) also showed a significant increase in bone density with respect to the OVX group, and the increase was almost equivalent to that of the iv-administered group of 0.625 nmol / kg of the same dose.

Then, urine deoxypyridinoline (DPD) and blood tartrate-resistant acid phophatase form 5b (TRACP 5b) were measured. DPD was corrected with urinary creatinine (DPD / CRe), and the results are shown in FIG. 8.

Urine DPD showed a tendency to decrease to 0.625nmol / kg of the iv-administered group of PTH (1-34), but increased to 0.625nmol / kg of the sc-administered group. In addition, in the blood TRACP 5b, only a dose of 2.5 nmol / kg of the iv-administered group was observed for the OVX group, and the results are shown in FIGS. 9A and 9B.

Osteocalcin (OC), a bone formation marker, was measured and the results are shown in FIG. 10. No significant change was observed between the OVX and sham groups, but a significant increase was observed for the OVX group at doses of 2.5 and 10 nmol / kg in the iv group and 0.625 nmol / kg in the sc group.

To investigate the effect of PTH (1-34) on bone turnover, bone morphology was performed. BV / TV, a parameter representing bone mass among the bone formation parameters, was observed in the iv administration group of PTH (1-34), and a dose-dependent increase was observed in the sc administration group (see FIG. 11A). ). In addition, Tb. In Th, a significant increase was observed at 2.5 and 10 nmol / kg of the iv administration group, while no significant increase was observed in the sc administration group (see FIG. 11B).

In ES / BS of bone resorption parameters, one of the bone morphometric parameters, a significant decrease was observed in the OVX group at 2.5 and 10 nmol / kg of the iv administration group of PTH (1-34), while in the sc administration group. Was not observed (see FIG. 12A). In N.Oc / BS of bone resorption parameters, a significant decrease was observed for the OVX group only at 2.5 nmol / kg of the PTH (1-34) iv administration group (see FIG. 12B).

In BFR / BS and LS / BS of bone formation parameters, one of the bone morphometric parameters, a significant increase was observed in the OVX group with respect to the sham group, and 2.5 and 10 nmol / kg of the iv-administered group of PTH (1-34). And a significant increase was observed for the OVX group in the sc-administered group, FIG. 13A shows BFR / BS, and FIG. 13B shows LS / BS.

From the above, PTH (1-34) was shown to increase the BMD in iv administration and sc administration, but it was found to have a different effect on bone metastasis. That is, in the iv-administered group of PTH (1-34), bone formation markers and bone formation parameters in bone morphometry were increased, while bone resorption markers and bone insorption parameters in bone morphology were decreased. It has been shown to inhibit bone resorption while promoting formation. On the other hand, in the sc-administered group of PTH (1-34), the bone formation parameters and bone formation parameters in the bone morphometry were increased, but the bone resorption parameters did not change, indicating that the sc-administered group did not inhibit the bone resorption.

As shown in Example 1, when the pharmaceutical composition comprising the hPTH of the present invention is administered by transmucosal mucosa, nausea, leg cramps, headache, dizziness, etc. Significantly lower the probability and frequency of onset of symptoms, and can maintain the action aimed at increasing the bone mass of hPTH, increasing bone density, inhibiting bone resorption, and the like. In addition, as shown in Examples 2 to 4, when the blood half-life of the administration method is short, it is possible to maintain both bone formation and bone resorption inhibitory effect of hPTH. For example, transmucosal administration or intravascular administration may be used as a short administration method for blood half-life. That is, when the pharmaceutical composition comprising the hPTH of the present invention is administered by a short administration method of blood half-life such as transmucosal administration, it is possible to maintain both the bone formation action and the bone repression inhibitory effect of hPTH.

All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

Claims (31)

Pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. The method of claim 1 Characterized in that the bone mass increase agent Pharmaceutical composition for transmucosal administration. The method of claim 1 Characterized in that it is a bone mineral density increasing agent Pharmaceutical composition for transmucosal administration. The method of claim 1 It is characterized in that the treatment for osteoporosis Pharmaceutical composition for transmucosal administration. The method of claim 1 It is characterized in that the bone resorption inhibitor Pharmaceutical composition for transmucosal administration. The method according to any one of claims 1 to 5 Promotes bone formation and suppresses bone resorption Pharmaceutical composition. The method according to any one of claims 1 to 6 Characterized in that it is a transnasal administration agent Pharmaceutical composition. The method according to any one of claims 1 to 7. hPTH is hPTH1-34, characterized in that Pharmaceutical composition. The method according to any one of claims 1 to 8. Characterized in that the daily dose is 250 μg to 1000 μg Pharmaceutical composition. The method according to any one of claims 1 to 8. Characterized in that the dosage is formulated to be from 250 μg to 1000 μg doing Pharmaceutical composition. To increase bone mass or bone density, and to inhibit an increase in the risk of developing one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, which is administered. Increasing bone mass or bone density, and inhibiting an increase in the probability of developing one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. It is administered to increase the bone mass or bone density, and to suppress the increase in the incidence of at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration , pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. characterized in that it is administered to lower the risk of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration while maintaining bone mass gain or bone density increase of hPTH. A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. characterized in that it is administered for the purpose of lowering the probability of onset of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration while maintaining the bone mass increase or bone density increase of hPTH. A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. characterized in that it is administered for the purpose of reducing the incidence of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration while maintaining the bone mass increase or bone density increase of hPTH. A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof. A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, which is administered for the purpose of maintaining both the bone formation action and the bone resorption inhibitory effect of hPTH. The method according to any one of claims 11 to 17. Transmucosal mucosa is characterized in that Pharmaceutical composition. The method according to any one of claims 11 to 18. hPTH is hPTH1-34, characterized in that Pharmaceutical composition. The method according to any one of claims 11 to 19. Characterized in that the daily dose is 250 μg to 1000 μg Pharmaceutical composition. The method according to any one of claims 11 to 19. Characterized in that the dosage is formulated to be from 250 μg to 1000 μg doing Pharmaceutical composition. hPTH or a derivative thereof is administered in the transmucosal membrane to reduce the risk of developing one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration. hPTH or a derivative thereof is administered in the transmucosal membrane to reduce the probability of developing at least one symptom selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration. hPTH or a derivative thereof is administered in the transmucosal membrane to reduce the incidence of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with hPTH administration. The method according to any one of claims 22 to 24. It is characterized by the fact that hPTH maintains bone mass increase or bone density increase. Gong Way. hPTH or a derivative thereof is administered in the transmucosal membrane to maintain both bone formation and bone resorption. 27. The method according to any one of claims 22 to 26. Transmucosal mucosa is characterized in that Way. A method of maintaining bone resorption inhibitory activity by administering hPTH or a derivative thereof by a method of short half-life in blood compared to subcutaneous administration. A method of maintaining bone formation and bone resorption by administering hPTH or a derivative thereof by a method of administration in which blood half-life is short compared to subcutaneous administration. 30. The method according to any one of claims 22 to 29 hPTH is hPTH1-34, characterized in that Way. The method according to any one of claims 22 to 30. Characterized in that the daily dose is 250 μg to 1000 μg Way.

Images