HK1101675A - Pth-containning preparation for transmucosal administration - Google Patents

Description

Transmucosal administration agent containing PTH

Technical Field

The present invention relates to a pharmaceutical composition for transmucosal administration containing human parathyroid hormone (hPTH) or an hPTH derivative as an active ingredient, and to a pharmaceutical composition capable of suppressing symptoms such as nausea occurring upon hPTH administration.

Background

Parathyroid hormone (PTH) is known to be one of the important hormones involved in bone metabolism. In the past, many reports have been made on the effects of PTH on bone.

Osteoporosis is a clinical condition in which low bone mass and microstructural changes in bone tissue result in a brittle bone and prone to fracture. It has been reported that fractures of the spine, femoral neck, radius, distal, etc. associated with osteoporosis lead to a reduction in quality of life (QOL), and in particular femoral fractures can be a cause of bedridden patients. Therefore, countermeasures against osteoporosis are required.

Various factors associated with bone fracture are intricate, and low bone density (low bone mass) is a major factor. Therefore, the importance of drug treatment of osteoporosis is to inhibit osteopenia and increase bone mass, resulting in the prevention of accidental fractures in high risk patients who are considered to have a high probability of causing fractures due to osteopenia.

Currently, commercially available drugs for treating osteoporosis include estrogen preparations, calcitonin preparations, preparations containing vitamin D active forms, ipriflavone preparations, vitamin K preparations, diphosphate preparations, and calcium preparations. However, most of these drugs are bone resorption inhibitors that inhibit promotion of bone resorption, and thus exhibit an effect of increasing bone mass. Thus, they are not osteogenic agents that act actively on bone formation and have the effect of increasing bone mass.

Human parathyroid hormone (hPTH) consists of an 84 amino acid sequence, a secreted calmodulin, which is secreted by the parathyroid gland in response to blood calcium levels. The body of hPTH physiological activity is reported to reside in the N-terminal 34 fragment (PTH1-34), which is involved in binding to the receptor.

Also, it is reported that the effect of hPTH on bone through basic and clinical studies is to promote bone resorption in the case of continuous administration and to promote bone formation in the case of intermittent administration. Therefore, hPTH is considered to have a mechanism of action different from that of the existing therapeutic drugs for osteoporosis, and thus it is a promising therapeutic drug for osteoporosis having a new mechanism.

However, it is reported that administration of hPTH to patients causes a certain proportion of nausea (paroxysmal vomiting, stomach upset, etc.), cramps, headaches, and dizziness (see non-patent documents 1 and 2). To prevent these symptoms, the hPTH dose administered to the patient may be reduced. In this case, the bone mass increasing effect of hPTH, i.e., its original purpose, is lost.

In order to reduce the symptoms of hPTH administration, it has been reported that an antiemetic such as teprenone can be incorporated (see patent document 1). However, this method can reduce only paroxysmal vomiting, stomach discomfort, etc. among various symptoms, and it is disadvantageous to administer one more drug.

Nasal pharmaceutical compositions containing hPTH have been reported (see patent documents 2 to 4), but the relationship with the above symptoms has not been described.

Therefore, there is a need for a method of administering hPTH which is useful for inhibiting symptoms such as nausea, leg cramps, headache, dizziness, while maintaining the bone mass increasing effect of hPTH.

Patent document 1: japanese patent laid-open (KoKai) No. 2003-95974A

Patent document 2: japanese patent publication (Kokai) No. 61-282320A (1986)

Patent document 3: japanese patent publication (Kokai) No. 4-247034A (1992)

Patent document 4: international publication No. WO02/021136 pamphlet

Non-patent document 1: neer et al, N.Eng.J.Med.344, 1434-

Non-patent document 2: fujita et al, Osteporosis int.9.296-306 (1996)

Disclosure of Invention

It is an object of the present invention to provide a method for suppressing symptoms such as nausea upon administration of the above PTH, and a pharmaceutical composition capable of suppressing the same.

The present inventors found that subcutaneous administration of hPTH causes symptoms such as nausea, cramping, headache and dizziness, and nasal administration of hPTH does not cause the onset of these symptoms or reduce the rate of onset of these symptoms while maintaining the effect of hPTH.

Thus, hPTH can be administered by transmucosal administration, such as nasal administration, to prevent, for example, nausea, leg cramps, headache and dizziness, while maintaining the bone mass-increasing effect of hPTH.

Namely, the present invention is as follows.

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

[2] [1] the pharmaceutical composition for transmucosal administration, wherein the composition is a bone mass increasing agent.

[3] [1] the pharmaceutical composition for transmucosal administration, wherein the composition is a bone density increasing agent.

[4] [1] the pharmaceutical composition for transmucosal administration, wherein the composition is a therapeutic agent for osteoporosis.

[5] [1] the pharmaceutical composition for transmucosal administration, wherein the composition is a bone resorption inhibitor.

[6] The pharmaceutical composition according to any one of [1] to [5], wherein the composition promotes osteogenesis and inhibits bone resorption.

[7] The pharmaceutical composition according to any one of [1] to [6], wherein the composition is nasally administered.

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

[9] The pharmaceutical composition according to any one of [1] to [8], wherein the dose of the composition per day is 250 μ g to 1,000 μ g.

[10] The pharmaceutical composition according to any one of [1] to [8], wherein the composition is prepared in a formulation in which the dose of the composition per day is 250 μ g to 1,000 μ g.

[11] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and inhibiting an increase in the risk of development of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

[12] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and suppressing the increase in the possibility of the occurrence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

[13] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and suppressing the high incidence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

[14] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered in order to maintain the effect of hPTH on bone mass increase or bone density increase and to reduce the risk of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

[15] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of maintaining the effect of hPTH on bone mass increase or bone density increase and reducing the possibility of the occurrence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

[16] A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered in order to maintain the effect of hPTH on bone mass increase or bone density increase and to reduce the incidence of one or more symptoms selected from the group consisting of leg cramps, nausea, headache and dizziness associated with the administration of hPTH.

[17] A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, wherein the composition is administered so as to maintain the effect of hPTH on both osteogenesis and bone resorption inhibition.

[18] The pharmaceutical composition according to any one of [11] to [17], wherein the transmucosal administration is through the nasal mucosa.

[19] The pharmaceutical composition according to any one of [11] to [18], wherein hPTH is hPTH 1-34.

[20] The pharmaceutical composition according to any one of [11] to [19], wherein the dose of the composition per day is 250 μ g to 1,000 μ g.

[21] The pharmaceutical composition according to any one of [11] to [19], wherein the composition is prepared in a formulation in which the dose of the composition per day is 250 μ g to 1,000 μ g.

[22] A method for reducing the risk of development of one or more symptoms selected from the group consisting of cramping, nausea, headache, dizziness associated with administration of hPTH, said method comprising transmucosal administration of hPTH or a derivative thereof.

[23] A method for reducing the likelihood of the development of one or more symptoms selected from the group consisting of cramping, nausea, headache, and dizziness associated with administration of hPTH, said method comprising transmucosal administration of hPTH or a derivative thereof.

[24] A method for reducing the incidence of development of one or more symptoms selected from the group consisting of leg cramps, nausea, headache, and dizziness associated with administration of hPTH, the method comprising transmucosal administration of hPTH or a derivative thereof.

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

[26] A method for maintaining both osteogenic and bone resorption inhibitory functions, comprising transmucosal administration of hPTH or a derivative thereof.

[27] The method of any one of [22] to [26], wherein the transmucosal administration is through the nasal mucosa.

[28] A method for maintaining a bone resorption suppressing function, which comprises administering hPTH or a derivative thereof by a shorter half-life in blood as compared with subcutaneous administration.

[29] A method for maintaining osteogenic and bone resorption inhibitory functions comprising administering hPTH or a derivative thereof in a manner such that the half-life in blood is shorter than that of subcutaneous administration.

[30] The method of any one of [22] to [29], wherein hPTH is hPTH 1-34.

[31] The method of any one of [22] to [30], wherein the dose of the composition per day is 250 μ g to 1,000 μ g.

As shown in example 1, transmucosal administration of the hPTH-containing pharmaceutical composition of the present invention significantly reduces the possibility and incidence of symptoms such as nausea, leg cramp, headache and dizziness, which are caused when administered by routes other than transmucosal administration. Also, target effects of hPTH such as bone mass increasing effect, bone density increasing effect, and bone resorption suppressing effect can be maintained.

Furthermore, as shown in examples 2 to 4, administration of a drug having a short half-life in blood can maintain both the osteogenic effect of hPTH and the bone resorption inhibitory effect. Examples of administration methods that provide a short blood half-life include transmucosal and intravascular administration.

That is, when the pharmaceutical composition containing hPTH of the present invention is administered by a method of administration providing a short half-life, such as transmucosal administration, both osteogenic and bone resorption inhibitory effects of hPTH are maintained.

The present specification includes the disclosure of the specification and/or drawings of japanese patent application 2004-207733, which is a priority document of the present application.

Drawings

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

FIG. 2A is a graph showing the change in blood PINP as an osteogenic marker at 6 weeks after administration;

fig. 2B is a graph showing changes in blood PINP as an osteogenic marker 12 weeks after administration;

FIG. 3A is a graph showing the change in urinary NTx as a marker of bone resorption 6 weeks after administration;

FIG. 3B is a graph showing the change in urinary NTx as a marker of bone resorption 12 weeks after administration;

FIG. 4 is a graph showing the effect of hPTH (1-34) in increasing lumbar vertebral density in elderly OVX rats;

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

FIG. 6 is a graph showing the effect of hPTH (1-34) on osteogenic markers in elderly OVX rats;

FIG. 7A is a graph showing the time course of hPTH (1-34) levels in blood when rats were administered intravenously;

FIG. 7B is a graph showing the time course of hPTH (1-34) levels in blood when rats were subcutaneously administered;

FIG. 8 is a graph showing the effect of hPTH (1-34) in increasing lumbar vertebral density in elderly OVX rats;

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

FIG. 9B is a graph showing the effect of hPTH (1-34) on the bone resorption marker (TRACP5B) in elderly OVX rats;

FIG. 10 is a graph showing the effect of hPTH (1-34) on an osteogenic marker (osteocalcin) in elderly OVX rats;

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

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

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

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

FIG. 13A is a graph showing the effect of PTH (1-34) on osteogenic parameters (BFR/BS) in elderly OVX rats; and

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

Best mode for carrying out the invention

Hereinafter, the present invention will be described in detail.

As described above, administration of hPTH is reported to increase the risk of occurrence of symptoms such as nausea, cramping, headache, dizziness, etc., and to increase the likelihood of the occurrence of the symptoms, or the frequency of the occurrence of the symptoms, as compared to administration of hPTH without administration.

The pharmaceutical composition for transmucosal administration of hPTH according to the present invention, which contains hPTH as an active ingredient, can reduce the risk of occurrence of symptoms such as nausea, leg cramp, headache, dizziness, etc., reduce the possibility of occurrence of the symptoms, and reduce the frequency of occurrence of the symptoms, while maintaining the effect of hPTH.

The maintenance of the effect is not limited by the extent of the effect, as long as the effect can be observed. Preferably, the effect is maintained to such an extent that a therapeutic effect is discernable (e.g., therapeutic effect on osteoporosis).

In the present invention, the expression "action of hPTH" means increase in bone mass, increase in bone density, inhibition of bone resorption, and the like. While hPTH retains these effects, it can be used for the purpose of treating osteoporosis or avoiding bone fracture. In the present invention, maintaining the effect of hPTH means that the effect of hPTH is observed in hPTH-administered patients when hPTH is administered. The bone mass increasing effect, bone density increasing effect, and bone resorption inhibiting effect can be measured by methods known to the skilled person, for example, by the methods described in the examples.

In the present invention, the expression "inhibiting an increase in the risk of developing symptoms" means inhibiting the risk of developing undesirable symptoms which increase upon administration of hPTH. In the present invention, the expression "inhibit increase" means to eliminate the increase itself or to reduce the degree of the increase. The expression "risk of developing symptoms" means the risk of undesirable symptoms that the administration of hPTH may cause. In the present invention, as a standard case, where hPTH is administered by a route of administration other than transmucosal administration (e.g., subcutaneous administration), a reduction in the risk of developing undesirable symptoms is considered to be "a reduction in the risk of developing symptoms".

According to the present invention, it has been found that transmucosal administration can reduce the risk of the occurrence of unwanted symptoms, which may be increased when hPTH is administered via a route of administration other than transmucosal administration (e.g., subcutaneous administration).

In the present invention, the expression "reducing the frequency of symptom development" means that the proportion of patients showing undesirable symptoms among the patient group administered with hPTH is reduced. Therefore, the frequency of symptom development refers to the proportion of patients who develop symptoms in the population of patients administered with hPTH. For example, when 10 patients among 100 patients administered with hPTH observed a certain symptom, the frequency of the symptom was 10%. In this case, "reducing the frequency of symptom production" means reducing the frequency by less than 10% (i.e., the symptom is observed in 9 patients or less).

Whether or not the frequency of symptom generation is reduced is judged based on the frequency of symptoms occurring when hPTH is administered via a route of administration (e.g., subcutaneous administration) different from transmucosal administration (particularly nasal administration).

More specifically, it has been reported that subcutaneous administration of hPTH1-34 results in 13%, 18%, 9% and 3% of the frequency of headache, nausea, dizziness and leg cramps, respectively (Robert M Neer et al, N EnglJ Med, 344(19), 1434-. Therefore, in a preferred embodiment of the present invention, for "reducing the frequency of symptom production": the frequency of headaches is reduced to less than 13%, preferably less than 10%, and more preferably less than 9%; the frequency of nausea is reduced to less than 18%, preferably less than 10%, more preferably less than 5%; the frequency of dizziness is reduced to less than 9%, preferably less than 7%, more preferably less than 6%; the frequency of leg cramps is reduced to less than 3%, preferably less than 2%, more preferably less than 1%.

For example, in the case of nasal administration, the frequency of occurrence of these symptoms is 7.2% of headache, 0% of nausea, 4.1% of dizziness, and 0% of cramp in legs, which are greatly reduced as compared with the case of subcutaneous administration, and therefore the risk of occurrence of the symptoms can be reduced.

In addition, the expression "reduce the possibility of occurrence of symptoms" in the present invention means that the possibility of occurrence of unnecessary symptoms is reduced in a certain patient. Therefore, in the case of "reducing the frequency of symptom generation", one population (patient population) is the subject. On the other hand, in the case of "reducing the possibility of symptom generation", a certain individual patient is the subject. Thus, the "probability of symptom generation" describes the probability that a patient will develop symptoms when hPTH is administered to the patient. In general, the "reduced likelihood of symptom development" or not can be determined by the proportion of patients who develop symptoms in the patient population to which hPTH is administered, in the same manner as "reduced frequency of symptom development". In addition, whether or not the probability of developing a symptom is reduced is determined based on the proportion of a population in which hPTH is administered via a route of administration (e.g., subcutaneous administration) other than transmucosal administration (particularly nasal administration) to produce a certain symptom. In the present invention, the number of persons in the population (patient group) is not limited, but is usually 5 or more patients, preferably 15 or more patients, more preferably 20 or more patients, and still more preferably 25 or more patients.

As described above, the pharmaceutical composition of the present invention is administered mucosally, and the possibility and frequency of symptom generation are reduced as compared with the case where the composition is administered by a route different from the route of administration via mucosal administration. For example, one or more symptoms selected from leg cramps, nausea, headache, and dizziness disappear, or the likelihood and frequency of the symptoms is reduced by nearly half.

In the present invention, the undesirable symptoms, which are the target of reducing the possibility and frequency of the onset thereof, are undesirable symptoms that occur at a high frequency when hPTH is administered via a route of administration other than transmucosal administration (e.g., subcutaneous administration). Examples include cramps, nausea (paroxysmal vomiting, stomach upset, etc.), headaches, and dizziness.

In addition, transmucosal administration, such as nasal administration of hPTH, can reduce the onset of the above-mentioned undesirable symptoms while maintaining the bone mass increasing, bone density increasing or bone resorption inhibiting effects of hPTH.

In addition, in general, inhibition of bone formation also occurs when hPTH administration inhibits bone resorption. Therefore, it is impossible to maintain both the bone resorption inhibitory effect and osteogenic effect of hPTH.

However, in the present invention, it has been found that hPTH can be administered by a method of administration which enables a short blood half-life, thereby maintaining both osteogenesis and bone resorption inhibitory effects of hPTH.

In the present invention, the administration method having a short half-life in blood is an administration method capable of shortening the half-life in blood as compared with subcutaneous injection. Specific examples of such methods include transmucosal administration (e.g., nasal administration) and intravascular administration (e.g., intravenous administration).

The blood half-life of the hPTH administration can be determined by methods known to the skilled artisan, and, for example, the blood half-life can be determined by the methods described in the examples.

Accordingly, the present invention relates to a method for maintaining the bone resorption inhibitory effect of administration of hPTH or a derivative thereof by an administration method which enables a short blood half-life, and in particular to a method for maintaining both the bone resorption inhibitory effect and the osteogenesis inhibitory effect.

A preferred embodiment of the present invention includes a method for both osteogenesis and bone resorption inhibition by transmucosal administration of hPTH or a derivative thereof.

The hPTH used in the present invention may be any hPTH, and examples thereof include full-length hPTH, hPTH derivatives, modified hPTH. In addition, examples include naturally occurring PTH, recombinant PTH produced by genetic engineering techniques, and chemically synthesized PTH.

Examples of the hPTH derivative include hPTH (1-84) (Biochemistry 17, 5723(1978), Kimura et al; Biochemistry, Biophys.Res. Commun., Vol.114, p.493, 1983), hPTH (1-38) (Japanese patent publication (Kokai) No. 57-81448A (1982), hPTH (1-34) (Japanese patent publication (Kokai) No. 9-29600A (1997); Takai et al, PeptideChemy, 1979, p.187), hPTH (1-34) NH₂(Japanese patent publication (Kokai) No. 58-96052A (1983)), [ Nle^8，18]hPTH(1-34)，[Nle^8，18，Tyr³⁴]hPTH (1-34) (Japanese patent laid-open (Kokai) No. 55-113753A (1980)), [ Nle^8，18]hPTH(1-34)NH₂(Japanese patent publication (Kokai) No. 61-24598A (1986)), [ Nle [^8，18，Tyr³⁴]hPTH(1-34)NH₂(Japanese patent laid-open (Kokai) No. 60-34996A (1985)), hPTH (1-37) (Japanese patent laid-open (Kohyo) No. 5-50559A (1993)), hPTH (2-84), hPTH (3-84), hPTH (4-84), hPTH (5-84), hPTH (6-84), hPTH (7-84) and hPTH (8-84) (Japanese patent laid-open (Kohyo) No. 4-505259A (1992)). In addition, examples of the hPTH of the present invention include those formed by the following method and having comparable activity: in the above-mentioned hPTH, some constituent amino acids are substituted with other amino acids, some constituent amino acids are deleted, and at least one amino acid is added to the constituent amino acids. Preferred examples of the amino acid substitution are substitution of the constituent amino acid at position 8 with leucine or norleucine, substitution of the constituent amino acid at position 18 with leucine or norleucine, and substitution of the constituent amino acid at position 34 with tyrosine.

Preferably, the hPTH of the present invention is hPTH (1-34).

hPTH can be produced by methods known to those skilled in the art. For example, it can be produced according to a method of genetic engineering technique or chemical synthesis technique (Japanese patent laid-open (Kohyo) No. 9-296000A (1997), Japanese patent No. 2643968, etc.). The produced hPTH can be purified by known techniques such as column chromatography. hPTH is a basic peptide, so an acid such as acetic acid can be used as an eluent to prevent hPTH from adsorbing onto the column resin. With acids at the time of purification, it is necessary to reduce the amount of acids in the pharmaceutical composition containing hPTH. The reduction of acid can be achieved by known methods such as dialysis, electrodialysis, ion exchange chromatography, gel filtration and reverse phase HPLC.

The pharmaceutical composition for transmucosal administration according to the present invention contains hPTH as an active ingredient, has good tolerance to formulation change, and thus can be appropriately mixed with ingredients generally used for formulations, such as carriers, excipients, thickeners, preservatives, stabilizers, antioxidants, binders, disintegrants, wetting agents, lubricants, colorants, flavors, corrigents, suspending agents, emulsifiers, solubilizers, buffers, hyperosmotics, surfactants, soothing agents, and sulfur-containing reducing agents. In addition, the pharmaceutical composition can be appropriately mixed with various functional ingredients for the purpose of improving absorption, solid stability, and the like.

Examples of carriers or excipients include substances which dissolve well or in small amounts in water, such as sugars, polysaccharides, dextrins, cellulose, synthetic or semi-synthetic polymers, amino acids, polyamino acids, proteins and phospholipids.

Examples of the sugar (monosaccharide, oligosaccharide) include D-mannitol, glucose, lactose, fructose, inositol, sucrose, maltose, and examples of the polysaccharide include dextran, pullulan, alginic acid, hyaluronic acid, tartaric acid, phytic acid, and phytin. Examples of dextrins include alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, dextrin, hydroxypropyl starch, and hydroxyethyl starch.

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

Examples of synthetic or semi-synthetic polymers include polyvinyl alcohol, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone (PVP), sodium polyacrylate, and polylactic acid.

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

Examples of proteins include gelatin and the like. In addition, chitin and chitosan may also be included.

Among these carriers or excipients, sucrose, maltose, α -cyclodextrin, β -cyclodextrin, dextrin, D-mannitol, inositol, lactose, dextran, methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and pullulan are particularly preferable.

In addition, sorbic acid; benzalkonium chloride (benzalconium chloride); cetylpyridinium chloride; benzethonium chloride; benzoates such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, isobutyl p-hydroxybenzoate and the like; gum arabic; sorbitol; magnesium stearate; talc; silicon dioxide; microcrystalline cellulose; starch; calcium phosphate; a vegetable oil; a carboxymethyl cellulose; sodium lauryl sulfate; water; ethanol; glycerin and syrup.

Typical examples of the surfactant are listed below. Wherein a single or a combination of two or more of these surfactants can be added to the formulation of the present invention. Examples of the nonionic surfactant include: sorbitol esters of fatty acids such as sorbitol monocaprylate, sorbitol monolaurate and sorbitol palmitate; glycerol esters of fatty acids, such as glycerol monocaprylate, glycerol monomyristate and glycerol monostearate; polyglycerol esters of fatty acids, such as decaglycerol monostearate, decaglycerol distearate, and decaglycerol monolinoleate; polyoxyethylene sorbitan esters of fatty acids, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate and polyoxyethylene sorbitan tristearate anhydride esters; polyoxyethylene sorbitol esters of fatty acids (polyoxyyethylene sobitol esters), such as polyoxyethylene sorbitol tetrastearate and polyoxyethylene sorbitol tetraoleate; polyoxyethylene glycerides of fatty acids, such as polyoxyethylene glyceryl monostearate; polyethylene glycol esters of fatty acids, such as polyethylene glycol distearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether (polyoxyethylenelauryl 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 (polyoxyethylated hydrogenated castor oil), such as polyoxyethylene castor oil and polyoxyethylene hardened castor oil (polyoxyethylene hydrogenated castor oil); polyoxyethylene beeswax derivatives such as polyoxyethylene sorbitol beeswax; polyoxyethylene lanolin derivatives, such as polyoxyethylene lanolin; and polyoxyethylene amides of fatty acids having an HLB of 6 to 18, such as polyoxyethylene stearamide. Examples of the anionic surfactant include alkyl sulfates having an alkyl group of 10 to 18 carbon atoms, such as sodium cetyl sulfate, sodium lauryl sulfate, and sodium oleyl sulfate; and polyoxyethylene alkyl ether sulfates, such as sodium polyoxyethylene lauryl sulfate, to which 2 to 4 moles of ethylene oxide and an alkyl group having 10 to 18 carbon atoms are added on average; and alkyl sulfosuccinate salts having 8 to 18 carbon atoms, such as sodium lauryl sulfosuccinate. Examples of naturally occurring surfactants include lecithin; a glycerophospholipid; sphingolipids, such as sphingomyelin; and sucrose esters of fatty acids containing 12 to 18 carbon atoms. Examples of sulfur-containing reducing agents include N-acetyl cysteine, N-acetyl homocysteine, lipoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, glutathione, thioalkanic acid (thioalkanic acid) having a mercapto group containing 1 to 7 carbon atoms.

Examples of antioxidants include erythorbic acid (erythorbic acid), dibutylhydroxytoluene, butylhydroxyanisole, alpha-tocopherol, tocopheryl acetate, levovitamin C and its salts, levovitamin C palmitate, levovitamin C stearate, sodium sulfite, tripentyl gallate, propyl gallate, and chelating agents such as disodium Ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.

The ratio of each component in the pharmaceutical composition according to the present invention, hPTH, may be about 0.01 to 20%, preferably 0.05 to 10%. The organic acid may be added as appropriate, and when added, may account for about 0.05 to 99.5%, preferably about 0.1 to 99.0%. The carrier or excipient usually used for preparing a pharmaceutical product may be added as appropriate, and, when it is added, it may occupy, for example, about 0.01 to 99.5%. Various other functional ingredients may be added as appropriate, and, in the case where they are added, they may occupy, for example, about 0.05 to 99.5%.

The pharmaceutical composition of the present invention contains hPTH as an active ingredient and can be administered by transmucosal administration. As long as the pharmaceutical composition is administered through the mucosa, any administration method may be used, for example, nasal administration, pulmonary administration, rectal administration, sublingual administration, and oral administration.

In the present invention, the preferred transmucosal administration is nasal administration.

The nasal administration preparation is not particularly limited, and examples thereof include droplets, sprays, aerosols, coatings, powders and gels. The composition is absorbed through the tissue and/or blood vessels in the nose and/or sinus tract (sinus tract).

The hPTH pharmaceutical composition for nasal administration can be produced by known methods (see WO02/02136, etc.).

The pharmaceutical composition of the present invention for nasal administration can be prepared by known methods.

For example, a pharmaceutical composition for hPTH having a low acetic acid content can be used as it is. Alternatively, a carrier or excipient which is generally used in the formulation, and an organic acid and other various functional ingredients may be added as appropriate, and mixed with the hPTH drug component having a low acetic acid content to form a product which can be used as a drug component. Mixing is performed by replacing the organic acid with acetic acid or simply adding. For example, a mixture containing a carrier or excipient generally used for formulation, an organic acid, and, if necessary, various functional ingredients, is first dissolved in distilled water together with the hPTH drug ingredient. The solution was then lyophilized to give a homogeneous composition.

Alternatively, the hPTH drug component, and if necessary, the carrier or excipient conventionally used in formulations, is first dissolved in distilled water and then lyophilized. Thereafter, the organic acid and various functional ingredients may be optionally added to the lyophilizate and dissolved together, followed by lyophilization to give a homogeneous composition.

As another alternative, the hPTH drug, together with the organic acid or various functional ingredients, is first dissolved in distilled water and then lyophilized. Then, a carrier or excipient which is generally used for formulation as necessary is dissolved together with the resulting product and lyophilized, thereby obtaining a homogeneous composition.

The pharmaceutical ingredient of the present invention may be formulated into various dosage forms according to the type of administration method, and may be formulated into dosage forms capable of transmucosal administration through the rectum, the nasal cavity, and the oral cavity. In addition, the nasally administrable pharmaceutical composition of the present invention is preferably administered in the form of a nasal drug.

A preferred example of the pharmaceutical composition for nasal administration of the present invention is a preparation which dissolves before use, which contains the pharmaceutical ingredient of the present invention as a lyophilized composition seeded in a lyophilized part, and has a dissolving solution part attached thereto.

The above-mentioned organic acids and absorption-promoting organic acids, citric acid, fatty acids and glycolic acid, may be part of the pharmaceutical composition of the present invention, as salts, adhesives, or additives of hPTH in the lyophilized fraction. Alternatively, these may be added and dissolved in the dissolution liquid portion.

In addition, the pharmaceutical composition for nasal administration of the present invention can be administered by a known method. For example, the nasally administrable pharmaceutical composition of the present invention may be contained in a formulation for use as a nasal drug. For example, by spraying the composition, intranasal administration may be employed. The container containing the pharmaceutical composition may be provided with a nebulizer, with the tip of the nozzle inserted into the nasal spray.

The dosage of the pharmaceutical composition may vary depending on the kind of disease, age and weight of the patient, severity of disease, and administration route. For example, when hPTH (1-34) is nasally administered, it can be administered once or several times per day for a plurality of consecutive days. Administration is preferably carried out such that a single dose contains hPTH (1-34) in an amount of 10. mu.g to 5,000. mu.g, preferably 250. mu.g to 1,000. mu.g. In addition, after a certain period of time of discontinuation, administration can be resumed depending on the symptoms.

In addition, the daily dose is not particularly limited, and those skilled in the art can make an appropriate judgment. Administration is carried out so that the amount of hPTH or derivative thereof per day is 250 to 1,000. mu.g. For such administration, the pharmaceutical composition is prepared such that a single dose contains, for example, 250 μ g to 1,000 μ g of the pharmaceutical composition of the present invention, and is then administered once a day.

Examples

The present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 Effect on patients with Primary osteoporosis

The effects of the pharmaceutical composition of the present invention were examined according to the following methods.

Subject: patient with primary osteoporosis

The scheme is as follows: comparative testing between randomly assigned parallel groups

The application method and the dosage are as follows: 250, 500 or 1,000 ug of hPTH (1-34) are nasally administered daily

Specifically, a lyophilized composition containing hPTH (1-34) is prepared so that it contains 250. mu.g, 500. mu.g or 1,000. mu.g of hPTH (1-34) in 200. mu.L of the drug solution when dissolved in a dissolution solution, and the prepared composition is dissolved and administered before use. Here, a nasally administrable preparation of hPTH (1-34) was produced by the method of example 2 of International patent publication No. WO 02/02136. The sprayer VP-7(Valois) can spray 100 μ L of medicinal liquid uniformly per pump, and spray the medicinal liquid once per nasal cavity, wherein the total amount of medicinal liquid sprayed per day is 200 μ L.

The examination method comprises the following steps: patients with primary osteoporosis were randomly assigned to three groups: 250 μ g, 500 μ g and 1,000 μ g. On consecutive 12-week days, a single dose was administered once daily containing a single amount of hPTH (1-34), and the effectiveness and safety of each amount was confirmed.

Evaluation of effectiveness: the rate of change of bone density (BMD), the rate of change of blood PINP as an osteogenic marker, and the rate of change of blood NTx as a bone resorption marker were evaluated over 12 weeks.

Specifically, the rate of change in bone density (L2-4BMD) of the second to fourth lumbar vertebrae evaluated 12 weeks after administration was measured by the DXA method, the rate of change in blood PINP as an osteogenic marker was measured by the RIA method, and the rate of change in urinary NTx as a bone resorption marker was measured by the ELISA method. For the assays of PINP and NTx, UniQ PINP RIA (available from OrionDiagnostica) and Osteomark (available from Mochida Pharmaceutical Co., Ltd.) were used, respectively.

And (3) safety evaluation: the number of occurrences of adverse events was calculated and evaluated.

The following results were obtained.

With respect to the rate of change (mean) of BMD after 12 weeks of administration, the 250-, 500-and 1,000- μ g fractions showed 0.14%, 0.69% and 2.44%, respectively, increasing in a dose-dependent manner. The rate of change was significantly increased in the 1,000- μ g group compared to the initial dose. In addition, the 1,000- μ g group showed a significantly high growth rate compared to the 250- μ g group. Fig. 1 shows the rate of change of BMD.

Regarding the rate of change (median) of blood PINP as an osteogenic marker at 6 weeks of administration, the 250-, 500-and 1,000- μ g fractions were shown to be 4.1%, 16.5% and 24.3%, respectively. Significant increases were observed in the 500- μ g and 1,000- μ g groups compared to pre-dose. The change rates at 12 weeks of administration were 1.4%, -0.84%, and 14.8% for the 250-, 500-, and 1,000- μ g groups, respectively. A significant increase was observed in the 1,000- μ g group compared to pre-dose. Figure 2 shows the rate of change of blood BINP.

Regarding the rate of change (median) of urinary NTx as a bone resorption marker at 6 weeks of administration, the 250-, 500-and 1,000- μ g groups showed-3.0%, -22.2% and-26.1%, respectively, and the rate of decrease was significantly greater in the 500- μ g group than in the 250- μ g group. Significant reductions were observed in the 500- μ g and 1,000- μ g groups compared to pre-dose. The change rates for the 250-, 500-and 1,000- μ g groups were-8.7%, -28.6% and-16.4%, respectively, at 12 weeks of administration. The reduction rate was significantly greater in the 500- μ g group than in the 250- μ g group. A significant decrease was observed in the 500- μ g group and the 1,000- μ g group compared to before the administration. FIG. 3 shows the rate of change of urinary NTx.

In calculating adverse and other events, the Preferred Terms (PTs) are encoded according to "MedDRA version 6.1" and the adverse event names are classified by System Organ Class (SOC).

Of 97 subjects evaluated for safety, 155 adverse events occurred in 70 (72.2%) subjects. The number of occurrences for each dose group was as follows: 22 of 31 subjects in the 250- μ g group (71.0%) had 46 events; 23 of 30 subjects in the 500- μ g group (76.7%) had 51 events; 20 (69.0%) of 29 subjects in the 1,000- μ g group had 48 events; and 5 (71.4%) of 7 subjects in the 1,500- μ g group had 10 events. Among them, events with an incidence of 5% or higher (PT indications) included 14 cases (14.4%) of nasopharyngitis events, 7 cases (7.2%) of headache events, 12 cases (12.4%) of supraventricular premature beat events and 5 cases (5.2%) of ventricular premature beat events. From the counts of SOC, 21 (21.6%) heart failure events, 19 (19.6%) clinical examination events, and 18 (18.6%) infectious and parasitic disease events were observed.

It was reported that leg cramps (3%), nausea (18%), dizziness (9%), headache (13%), etc. were observed by subcutaneous administration (refer to Robert M Neer et al, N Engl Med, 344(19), 1434-.

As for side effects, 37 events occurred in 24 subjects (24.7%). The number of occurrences for each dose group was as follows: 7 (22.6%) of 31 subjects in the 250- μ g group had 12 events; of 30 subjects in the 500- μ g group 8 (26.7%) had 10 events; 7 (24.1%) of 29 subjects in the 1,000- μ g group had 13 events; and 2 (28.6%) of 7 subjects in the 1,500- μ g group had 2 events. Among them, no events with an incidence of 5% or more were observed.

From the results of effectiveness and safety in clinical examination, it was concluded that the agent significantly increases BMD by promoting osteogenesis and inhibiting bone resorption, and has excellent safety.

Example 2 Effect of tail vein administration of PTH (1-34) to aged OVX rats on bone metabolism

Elderly OVX rats were administered (i.v.) PTH (1-34) via the tail vein and examined for the effect of PTH (1-34) on bone metabolism.

Female SD-IGS rats (Charles River Japan, Inc.) at 34 weeks of age were Ovariectomized (OVX) to remove bilateral ovaries or sham surgery. At 48 weeks of age, bone density was determined in the OVX group and divided into 8 rats per group to make the mean BMD of each group consistent.

hPTH (1-34) was diluted in Phosphate Buffered Saline (PBS)/0.05% Tween 80 and adjusted to 10, 2.5, 0.625 nmol/ml. Each of 8 rats in the sham and OVX groups was dosed with Phosphate Buffered Saline (PBS)/0.05% Tween 80. Each group of 8 rats was dosed at 1ml/kg (10, 2.5, 0.625nmol/kg) with diluted hPTH (1-34) via the tail vein for a period of 6 weeks on a 5 weekly basis. On the last day of dosing, rats were housed in metabolic cages and 24 hours of urine was collected from each rat. The following day, rats were euthanized by exsanguination under anesthesia and a necropsy was performed to collect blood, lumbar vertebrae and femurs. Urine and blood were placed in test tubes and centrifuged to collect the respective supernatants, stored at-20 ℃ until parameter analysis. Lumbar vertebrae and right femur were preserved in 70% ethanol. The average bone density of the second to fifth lumbar vertebrae and the bone density of the right femur were measured by a dual-energy X-ray bone densitometer (DCS-600EX, ALOKA). Serum and urine were assayed for markers of bone metabolism. Fig. 4 shows the results.

As shown in FIG. 4, the OVX group showed a significant decrease in lumbar bone density compared to the sham group. In addition, hPTH (1-34) administration resulted in a significant, dose-dependent increase in waist bone density in the OVA group.

Next, deoxypyridinol (DPD) in urine was measured as a bone resorption marker. Fig. 5 shows the results. DPD was corrected for urinary creatinine values. As for urinary DPD, a significant decrease was observed in the group administered intravenously with 0.625nmol/kgPTH (1-34). However, no significant decrease was observed at the 2.5nmol/kg and 10nmol/kg doses.

Then, hemoosteocalcin (OC) was measured as an osteogenic marker. Fig. 6 shows the results. The OVX group showed a significant increase over the sham group. In addition, significant increases also appeared in the 2.5nmol/kg and 10nmol/kg dose groups of the PTH (1-34) administered group compared with OVX.

As described above, intravenous administration of PTH (1-34) increased BMD with increased markers of osteogenesis and decreased markers of bone resorption. This suggests that intravenous administration of PTH (1-34) inhibits bone resorption at low doses.

Example 3 changes in plasma PTH (1-34) levels following tail vein and subcutaneous administration

Changes in plasma PTH (1-34) levels following tail vein (iv) and subcutaneous (sc) administration were examined. hPTH (1-34) was diluted in Phosphate Buffered Saline (PBS)/0.05% Tween 80 and adjusted to 10 nmol/ml. Female SD-IGS rats (Charles River Japan, Inc.) of 8 weeks of age were used for the experiments. Single dose administration was performed in the tail vein (iv) and subcutaneous (sc) administration, and blood was collected from the tail vein in a time-dependent manner using a blood collection capillary (2.5, 5, 7.5, 10, 15, 30, 60, 120min before administration). After EDTA, plasma was separated and the collected blood samples were stored at-80 ℃ until hPTH (1-34) levels were determined. PTH (1-34) levels were determined by ELISA using PTH (1-34) (human) -EIA kit (Peninsula Laboratories). The changes in plasma levels of PTH (1-34), as well as the pharmacokinetic parameters calculated therefrom, are shown in FIGS. 7A and 7B, as well as in Table 1.

It was demonstrated that hPTH (1-34) showed more pulse-like Pharmacokinetics (PK) with iv administration than with sc administration.

TABLE 1 pharmacokinetic parameters of hPTH (1-34)

	Tmax(min)	Cmax(min)	T1/2(min)	AUC(ng/mL*min)
					ivsc	-20	-9.0	6.910.8	1066230

Example 4 difference in the Effect of old OVX rats on bone turnover by Tail vein administration and subcutaneous administration of PTH (1-34)

(iv) and subcutaneous (sc) administration of PTH (1-34) to the tail vein of the aged OVX rats, and examination of the difference in bone-renewal effect caused by the difference in PK of PTH (1-34).

hPTH (1-34) was dissolved in 10mM acetic acid solution and adjusted to 10nmol/mL aliquots with 25mmol/L phosphate-citrate buffer, 100mmol/L NaCl, 0.05% Tween 80 buffer (pH 5.0). The resulting solution was stored at-80 ℃ until use.

Bilateral ovaries were removed with 33-week-old female SD-IGS rats (Charles River Japan, Inc.), 60 lines of Ovariectomy (OVX), and 8 lines of sham surgery. After 28 weeks, OVX groups were assayed for bone density and subdivided into 8 groups, such that the average BMD was the same for all groups.

The preserved hPTH (1-34) was diluted with the phosphate-citrate buffer, and hPTH (1-34) was adjusted to 10, 2.5, and 0.625 nmol/mL. Buffer was administered to one OVX group of sham and 8 rats. The diluted hPTH (1-34) was administered iv to each of the 8 rat groups at a dose of 1ml/kg (10, 2.5, and 0.625nmol/kg) over a period of 6 weeks on a 5 weekly basis. In addition, one group was administered hPTH (1-34) at a dose of 1mL/kg (0.625nmol/kg) at a rate of 0.625nmol/mL over a 6-week period on a 5-weekly basis. On the last day of dosing, rats were housed in metabolic cages and 24 hours of urine was collected from each rat. The following day, rats were euthanized by exsanguination under anesthesia and a necropsy was performed to collect blood, lumbar vertebrae and femurs. Urine and blood were placed in test tubes and centrifuged to collect the respective supernatants, stored at-20 ℃ until parameter analysis. Lumbar vertebrae and right femur were preserved in 70% ethanol. The average bone density of the second to fifth lumbar vertebrae and the bone density of the right femur were measured by a dual-energy X-ray bone densitometer (DCS-600EX, ALOKA). In addition, bone morphology was measured for the third lumbar vertebra. Serum and urine were assayed for markers of bone metabolism. Fig. 8 shows the results.

As shown in fig. 8, the OVX group showed a significant decrease in lumbar bone density compared to the sham group. Also, the hPTH (1-34) group administered intravenously showed a significant and dose-dependent increase in lumbar bone density compared to the OVX group. In addition, the hPTH (1-34) subcutaneous group showed a significant increase in bone density compared to the sham group, and this increase was almost the same as that of the intravenous administration at a dose of 0.625 nmol/kg.

Urodeoxypyridinol (DPD) and tartrate-resistant acid phosphatase form 5b (TRACP5b) were determined as bone resorption markers. DPD was corrected for urinary creatinine values (PPP/Cre). The results are shown in FIG. 8.

With respect to urinary DPD, a decreasing trend was observed in the group administered intravenously at 0.625nmol/kg PTH (1-34), while an increasing trend was observed in the group administered subcutaneously at 0.625 nmol/kg. With respect to blood TRACP5b, a significant decrease was observed only in the 2.5nmol/kg intravenous group compared to the OVX group. The results are shown in FIGS. 9A and 9B.

Determination of blood Osteocalcin (OC) as an osteogenic marker. The results are shown in FIG. 10. No significant changes were observed between OVX and sham groups. However, the intravenous group at the 2.5nmol/kg and 10nmol/kg doses, and the subcutaneous group at 0.625nmol/kg showed a significant increase over the OVX group.

To investigate the effect of PTH (1-34) on bone turnover, bone morphometry was performed. Among the bone morphometry parameters, BV/TV is a parameter indicating bone mass. A clear, dose-dependent increase in BV/TV occurred in the PTH (1-34) intravenously administered group, whereas no significant increase was seen in the subcutaneously administered group (FIG. 11A). Also, with respect to the parameter tb.th indicating bone mass, significant increases were observed in the intravenous administration groups at the 2.5nmol/kg and 10nmol/kg doses, while no significant increase was observed in the subcutaneous administration group (fig. 11B).

Regarding the bone resorption parameter ES/BS, which is one of bone morphometric parameters, a significant decrease in PTH (1-34) levels at 2.5nmol/kg and 10nmol/kg doses was observed in the intravenous administration group as compared with the OVX group, while no significant decrease was observed in the subcutaneous administration group (FIG. 12A). Regarding the bone resorption parameter N.Oc/BS, a significant decrease was observed in the OVX group only in the PTH (1-34) intravenously dosed at 2.5nmol/kg (FIG. 12B).

With respect to the osteogenic parameters BFR/BS and LS/BS, which are one of the bone morphogenetic parameters, a significant increase was observed in the OVX group compared to the sham group. In the 2.5nmol/kg and 10nmol/kg dose PTH (1-34) intravenously administered group, as well as in the PTH (1-34) subcutaneously administered group, a significant increase was observed compared to the OVX group. FIGS. 13A and 13B show the measured parameters BFR/BS and LS/BS, respectively.

Based on the foregoing, it has been revealed that intravenous and subcutaneous administration of PTH (1-34) shows an effect of increasing BMD, but it shows different effects in bone turnover. That is, the PTH (1-34) intravenous administration group increased the osteogenic markers and the osteogenic parameters for bone morphogenesis and decreased the bone resorption markers and the bone morphogenetic parameters. This indicates that the group administered intravenously inhibited bone resorption while promoting bone formation. On the other hand, although subcutaneous administration of PTH (1-34) increased the osteogenic parameters for osteogenic labeling and bone morphogenesis determination, no change in bone resorption parameters was seen. This indicates that the subcutaneous administration group did not inhibit bone resorption.

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

Claims (31)

1. A pharmaceutical composition for transmucosal administration, comprising hPTH or a derivative thereof.

2. The pharmaceutical composition for transmucosal administration according to claim 1, wherein the composition is a bone mass increasing agent.

3. The pharmaceutical composition for transmucosal administration according to claim 1, wherein the composition is a bone density increasing agent.

4. The pharmaceutical composition for transmucosal administration according to claim 1, wherein the composition is a therapeutic agent for osteoporosis.

5. The pharmaceutical composition for transmucosal administration according to claim 1, wherein the composition is a bone resorption inhibitor.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition promotes osteogenesis and inhibits bone resorption.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is nasally administered.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein hPTH is hPTH 1-34.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is in a dose of 250 μ g to 1,000 μ g per day.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is formulated in a daily dose of 250 μ g to 1,000 μ g.

11. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and inhibiting an increase in the risk of development of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

12. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and suppressing the increase in the possibility of the occurrence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

13. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of increasing bone mass or bone density and preventing a high incidence of development of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

14. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of maintaining the effect of hPTH on bone mass increase or bone density increase and reducing the risk of development of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

15. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of maintaining the effect of hPTH on bone mass increase or bone density increase and reducing the possibility of occurrence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

16. A pharmaceutical composition for transmucosal administration comprising hPTH or a derivative thereof, wherein the composition is administered for the purpose of maintaining the effect of hPTH on bone mass increase or bone density increase and reducing the incidence of one or more symptoms selected from the group consisting of leg cramp, nausea, headache and dizziness associated with the administration of hPTH.

17. A pharmaceutical composition for transmucosal administration containing hPTH or a derivative thereof, wherein the composition is administered for the purpose of maintaining the effect of hPTH on both osteogenesis and bone resorption inhibition.

18. The pharmaceutical composition according to any one of claims 11 to 17, wherein transmucosal administration is through the nasal mucosa.

19. The pharmaceutical composition according to any one of claims 11 to 18, wherein hPTH is hPTH 1-34.

20. The pharmaceutical composition according to any one of claims 11 to 19, wherein the composition is administered at a daily dose of 250 μ g to 1,000 μ g.

21. The pharmaceutical composition according to any one of claims 11 to 19, wherein the composition is formulated in a daily dose of 250 μ g to 1,000 μ g.

22. A method for reducing the risk of development of one or more symptoms selected from the group consisting of cramping, nausea, headache and dizziness associated with administration of hPTH, said method comprising transmucosal administration of hPTH or a derivative thereof.

23. A method for reducing the likelihood of the development of one or more symptoms selected from the group consisting of cramping, nausea, headache and dizziness associated with administration of hPTH, said method comprising transmucosal administration of hPTH or a derivative thereof.

24. A method for reducing the incidence of development of one or more symptoms selected from the group consisting of leg cramps, nausea, headache and dizziness associated with administration of hPTH, said method comprising transmucosal administration of hPTH or a derivative thereof.

25. The method according to any of claims 22 to 24, wherein the effect of hPTH on bone mass increase or bone density increase is preserved.

26. A method for maintaining both osteogenic and bone resorption inhibitory functions, comprising transmucosal administration of hPTH or a derivative thereof.

27. The method of any one of claims 22 to 26, wherein transmucosal administration is through the nasal mucosa.

28. A method for maintaining a bone resorption suppressing function, comprising administering hPTH or a derivative thereof by a method of administration which has a shorter blood half-life than subcutaneous administration.

29. A method for maintaining osteogenic function and bone resorption suppressing function, which comprises administering hPTH or a derivative thereof by a method of administration having a shorter blood half-life than that of subcutaneous administration.

30. The method of any one of claims 22 to 29, wherein hPTH is hPTH 1-34.

31. The method according to any one of claims 22 to 30, wherein the composition is administered at a daily dose of 250 μ g to 1,000 μ g.