CA2145302C - Peptide proteinaceous drug nasal powder composition - Google Patents
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- CA2145302C CA2145302C CA002145302A CA2145302A CA2145302C CA 2145302 C CA2145302 C CA 2145302C CA 002145302 A CA002145302 A CA 002145302A CA 2145302 A CA2145302 A CA 2145302A CA 2145302 C CA2145302 C CA 2145302C
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B60—VEHICLES IN GENERAL
- B60H—ARRANGEMENTS OF HEATING, COOLING, VENTILATING OR OTHER AIR-TREATING DEVICES SPECIALLY ADAPTED FOR PASSENGER OR GOODS SPACES OF VEHICLES
- B60H1/00—Heating, cooling or ventilating [HVAC] devices
- B60H1/00485—Valves for air-conditioning devices, e.g. thermostatic valves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/25—Growth hormone-releasing factor [GH-RF] (Somatoliberin)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Abstract
A peptide proteinaceous drug nasal powder composition containing (i) an absorption accelerant comprised of a compound, or its salt, having in its molecule a group expressed by the formula (I):
(see formula I) wherein, (see formula II) indicates a cyclohexane ring or a benzene ring which may be substituted at least one of its 3-position, 4-position, and 5-position and n is an integer of 1 to 3 and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
(see formula I) wherein, (see formula II) indicates a cyclohexane ring or a benzene ring which may be substituted at least one of its 3-position, 4-position, and 5-position and n is an integer of 1 to 3 and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
Description
DESCRIPTION
Peptide Proteinaceous Drug Nasal Powder Composition TECHNICAL FIELD
The present invention relates to a peptide proteinaceous drug nasal powder composition having an improved absorbency. More specifically, it relates to a peptide proteinaceous drug nasal powder composition, which is improved in absorption from the mucous membrane of the nasal cavity to the blood stream of the entire body by suppression of the decomposition of the peptide proteinaceous drug administered to the nasal cavity by an absorption accelerant having specified groups.
BACKGROUND ART
Along with the progress in biotechnology in recent years, there have been a succession of discoveries of peptide roteinaceous compounds having physiological activity. Production of these compounds has become easy as well. Many of these peptide proteinaceous drugs are used only as injections due to the low level of their stability and absorbency. However, these drugs are preferably administered in multiple dosages for therapeutic reasons. Administration by injection in this case places a burden on the patient due to the pain to the patient and the need for visiting a hospital.
Therefore, other various methods of administration have been examined as non-invasive methods of administration of peptide proteinaceous drugs to take the place of injections, for example, the method of rectal administration by suppositories (J. Pharma., 33 334 (1981)), bronchial administration (Diabetes 20 552 (1971)), instillation administration (Abstracts of Diabetes Society 237 (1964)), etc. All of these methods, however, are hard to commercialize due to the difficulties that higher dosages are required than with injections and the absorption tends to fluctuate.
On the other hand, the nasal cavity has a well '~- 2145302 developed system of blood vessels in the mesothelium layer and is able to absorb a drug quickly and with little variation. Due to these advantages, the nasal administration method has come into attention. At the present time, however, sufficient absorption cannot be obtained, and therefore, various studies are under way to raise the absorbency.
For example, Nolte et al. (Hormone Metabolic Research 22, 170-174, 1990), Moses (Pharmaceutisch Week-blad-Scientific Edition 10, 45-46, 1988), Bruce et al. (Diabetic Medicine 8, 366-370,1991), etc. report on nasal administration of insulin containing sodium glycocholate or sodium taurofusidate as absorption accelerants. These preparations containing absorption accelerants, however, have problems with irritation to the nasal mucous membrane, and therefore, have not been commercialized.
As the major causes for the low absorbency of a peptide proteinaceous drug from the nasal mucous membrane, Illum (Trends Biotechnol 9, 284-289, 1991), W.A. Lee (Biopharm. Manuf. 1, 30-37, 1988), Edman (Advanced Drug Delivery Reviews 8, 165-177, 1992), etc.
have mentioned the low level of drug permeability into the mucous membrane, the elimination of the drug by ciliary movement, and the degradation of the drug by the protease in the nasal cavity.
Among these, as a major discovery relating to the protease in the nasal cavity, 0' Hagan et al. (Pharm.
Res. 7, 772 (1990)), Hussain et al. (Pharm. Res. 6, 186 (1989)), showed by animal experiments using rats and sheep that the nasal absorption of insulin, growth hormone, enkephalin, and other peptide proteinaceous drugs is improved by administration together with amastatin, bestatin, a-aminoboronic acid, or other aminopeptidase inhibitors.
Further, Illum et al. (Japanese National Disclosure (Kohyo) No. 2-503915) mentioned that effective protease inhibitors for nasal preparations in studies of rats, rabbits, and sheep were actinonin, amastatin, bestatin, chloroacetyl-HO-Leu-Ala-Gly-NH2, diprotin A and B, evelactone A and B, E- 64, H-(tBu)-Phe-Pro-OH, kallikrein inhibitor I, chymotrypsin inhibitor I, trypsin inhibitor III - 0, leupeptin, pepstatin, phosphoramidone, aprotinin, chymostatin, and benzamidine.
Further, Morimoto et al. (111 and 112 Ann. Meetings of JPN Pharm, Soc.) showed by by animal experiments using rats that the nasal absorbency of salmon calcitonin was improved by administering it with aprotinin, TAME (tosyl arginine methyl ester), which was a synthetic substrate of trypsin, or other trypsin inhibitors.
Further, the present inventors confirmed by animal experiments using rabbits that in the nasal cavity of rabbits, salmon calcitonin, LHRH, insulin, and other peptide proteinaceous drugs were cleaved at the C
terminal of the Leu in their primary structures and that the nasal absorbency of these is improved by administering them with a chymotrypsin inhibitor (for example, see Japanese Patent Application No. 5-130993 i.e., Japanese Unexamined Patent Publication No. 6-321804.
These findings, however, were all based on animal experiments using rats, sheep, and rabbits and the significance for humans is unclear. Accordingly, at the present time, it is not clear if the methods for improving the nasal absorbency of peptide proteinaceous drugs in rats, sheep, rabbits, and other animals would be effective for humans.
DISCLOSURE OF INVENTION
Accordingly, the present invention provides a peptide proteinaceous drug nasal powder composition which, by combined use of a protease inhibitor, suppresses the degradation of the peptide proteinaceous drug in the human nasal cavity by the action of the enzyme, is improved in the nasal absorbency, and is safe to the body.
In accordance with the present invention, there is provided a peptide proteinaceous drug nasal powder composition comprising (i) an absorption accelerant comprising a compound, or its salt, having in its molecule a group expressed by the formula (I):
4 ( I ) NH2- (CH2)~ 0 (wherein, - indicates a cyclohexane ring or a benzene ring which may be substituted at least at one of its 3-position, 4-position, and 5-position and n is an integer of 1 to 3) and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
In accordance with one embodiment of the present invention there is provided a peptide proteinaceous drug nasal powder composition comprising (i) an absorption accelerant comprising a compound, or its salt, having in the compound molecule a group expressed by the formula (II):
RI
; '.
NHZ - (CI-i2)n RZ
(II) ; ', wherein represents a cyclohexane ring or a benzene ring; n is an integer of 1 or 2; R', R2 and RI are, independently, a member selected from the group consisting - 4a -of a hydrogen atom -COOR, -COR, -OR', and -SOzNH2, which may be substituted; provided that at least one of R1, R' or R3 is a hydrogen atom; R represents a hydrogen atom, a C1-Ce lower alkyl group which may be substituted, or -( U}- CH2CH2COOR' , R' represents a hydrogen atom, a C1-C6 loweralkyl group which may be substituted, a phenyl group which may be substituted, or a C7-C8 aralkyl group which may be substituted, and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will now be explained in further detail with reference to the drawings; wherein:
Figure 1 is a graph showing the changes along with time of the concentration of salmon calcitonin in the plasma in normal human volunteers after administration of a calcitonin nasal powder composition;
Figure 2 is a graph showing the changes along with time of the concentration of GH in the plasma in normal human volunteers after administration of a GHRH nasal powder composition;
Figure 3 is a graph showing the changes along with time of the concentration of LH in the plasma in normal human volunteers after administration of an LHRH nasal powder composition;
Figure 4 is a graph showing the changes along with time of the concentration of salmon calcitonin in the plasma in normal human volunteers in Example 4 after ~, -administration of a calcitonin nasal powder composition;
and Figure 5 shows the concentration of calcitonin in the plasma in the case of administration of nasal preparations of the present invention in Examples 5 and 6 and nasal preparations in Control Examples 1 and 2.
BEST MODE FOR CARRYING OUT THE INVENTION
As mentioned above, the present inventors found that a compound having the specific formula (I) suppressed the degradation of peptide proteinaceous drugs in the human nasal cavity and improves the nasal absorbency.
It should be noted that, as is clear from the later Reference Experiments and Examples, the compound having the above-mentioned formula (I), that is, the absorption accelerant for providing a peptide proteinaceous drug preparation which suppresses the degradation of peptide proteinaceous drug in the human nasal cavity by the action of the protease and improves the nasal absorbency, as aimed at by the present invention, may be said to be a compound where the aminomethyl group, aminoethyl group, and aminopropyl group have attached to them a cyclohexane ring or benzene ring that cannot cover these groups spatially due to the intermolecular electrostatic interaction or rigidity etc. Accordingly, also included in the absorption accelerant of the present invention are compounds in which the substituents and cyclohexane and benzene are substituted by other substituents, for example, chain (straight chain, branched) or cyclic saturated or unsaturated hydrocarbon groups etc. to the extent to which it is naturally assumed that these groups will not be covered spatially due to the intermolecular electrostatic interaction or rigidity etc.
That is, the compound of formula (I) has a NH2-(CH2)a-group. It is essential that this is bonded together with a cyclohexane ring or benzene ring. With just this structure, the cyclohexane ring or benzene ring ~. -may have a substituent at the 3-, 4-, and/or 5-position three-dimensionally separated from the NHZ-(CH2)a-group.
The substituent is not particularly limited so long as it is a group which is stable as a preparation in the case of being made a powder and which poses no safety problem in terms of irritation etc. when administered to a human patient. More specifically, the compound having the group of the structure of formula (I) may be expressed by the following general formula (II):
R' NH:-(CH:). R' (II) R' wherein, n is an integer of 1 to 3, preferably 1 to 2, and R1, RZ, and R3 are, independently, a group selected from a hydrogen atom, phosphoric acid group, cyano group, COOR, COR, OR', S(0)PR', NR'R", carbamoyl group, S02NHZ, and substitutable C1-C20 hydrocarbon group, wherein R
represents a hydrogen atom; C1-C6 lower alkyl group which may be substituted; or - CHZCHZCOOR', R' and R"
epresent, independently, a hydrogen atom; C1-C6lower alkyl group which may be substituted, phenyl group which may be substituted, or C7-C8 aralkyl group which may be substituted, and p is an integer of 0 to 3.
In these Rl to R3, as the C1-C6 lower alkyl group, mention may be made of a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, and other straight chain or branched chain or cyclic alkyl groups. Among these, a methyl group, ethyl group, n-butyl group, and other C1-C4 lower alkyl groups may be mentioned as being preferable. Further, as the C7-C8 aralkyl group, mention may be made of a benzyl group and phenylethyl group.
_2145302 Further, the C1-C20 hydrocarbon group means a saturated or unsaturated chain (straight chain or branched) or cyclic hydrocarbon group. For example, mention may be made of those similar to those illustrated as the C1-C6lower alkyl group and those which, when unsaturated, have one or more double bonds and/or triple bounds, such as a heptyl group, decyl group, eicosyl group, 2,2-dimethyloctyl group, cyclohexylbutyl group, propenyl group, isopentenyl group, 8-heptadecenyl group, and 8,11-heptadecadienyl group. As the C1-C20 hydrocarbon group, preferably, mention may be made of a Ci-C15 hydrocarbon group, more preferably a C1-Clo hydrocarbon group.
As a specific example of the COOR of the R' to R3, mention may be made of a carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, hexyloxycarbonyl group, and - C00 CHZCH2COOR' and as a specific example of the COR, mention may be made of formyl group, acetyl group, propionyl group, and CO CH2CH2COOR'.
Further, as specific examples of the S(0)PR', mention may be made of a thiol group, sulfenic acid group, sulfinic acid group, sulfonic acid group, methylthiol group, isopropyl thiol group, isopropyl sulfinyl group, isopropyl sulfonyl group, pentyl sulfonyl group, phenyl thiol group, phenyl sulfonyl group, etc.
Further, as specific examples of NR'R", mention may be made of an amine group, dimethyl amine group, diethyl amine group, benzyl amine group, phenethyl amine group, etc.
Further, as specific examples of the OR', mention may be made of a hydroxyl group, methoxyl group, ethoxyl group, (n-, i-) propoxyl group, (n-, i-, s-, t-) butoxyl group, hexyloxyl group, cyclopropylmethyloxyl group, phenyloxyl group, phenethylloxyl group, etc.
_2145302 The R' to R3 of the present invention may, when having a C1-C20 hydrocarbon group; C1-C6 lower alkyl group, phenyl group, or C7-C8 aralkyl group, further have substituents at these groups. As such substituents, mention may be made of the phosphoric acid group, cyano group, COOR, COR, OR', S(0)pR', NR'R", carbamoyl group, and SOZNH2 exemplified as R' to R3.
As the absorption accelerant of the present invention, mention may be made of the compounds in formula (I) or (II), wherein n = 1 or 2 mentioned as preferable.
As the substituent on the cyclohexane ring or benzene ring in the above-mentioned formula (I) or (II), mention may be made of a substituent selected from COOR, COR, OR', SO2NH2 and a C1-Cio hydrocarbon group among those illustrated as R1 to R3.
In particular, in the above-mentioned formula (I) or (II), when the cyclic structure is a cyclohexane ring and n =1, preferable mention may be made of a compound wherein the substituent is a group selected from among the group comprising a hydrogen atom, COOR, and COR. In particular, preferable mention may be made of a group selected from the group comprising a hydrogen atom, carboxyl group, C00 _~a CH2CH2COOH, and CO -4a CH2CH2COOH
In this case, specific mention may be made of the case where as the substituents as R' to R3, R1 to R3 are hydrogen atoms or R1 and R3 are hydrogen atoms and R 2 is a group other than a hydrogen atom.
Further, when the cyclic structure is a benzene ring and n = 1 or 2 in the above-mentioned formula (I) or (II), preferable mention may be made of a compound wherein the substituent is a group selected from the group comprising a hydrogen atom, SOZNH2, and OR', in particular, mention may be made of the case where n = 1 _2145302 and the substituent is a group selected from a hydrogen atom, carboxyl group, and SO2NH2(sulfamine) group or n 2 and the substituent is a hydrogen atom or hydroxyl group. In this case, specific mention may be made of the case where as the substituents as R1 to R3, when n = 1, R1 to R3 are hydrogen atoms or R1 and R3 are hydrogen atoms and R 2 is a carboxyl group or SOZNHZ group or, when n = 2, R1 is a hydrogen atom and R 2 and R3 are hydroxyl groups.
As further preferable examples of the compounds having the formula (I), mention may be made for example of cyclohexane methylamine, benzylamine, p- aminomethyl benzoic acid, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and their derivatives and acid addition salts and other salts.
Tranexamic acid has been known as a hemostyptic and is used at the time of abnormal bleeding caused by systemic hyperfibrinolysis. Its safety in the body has already been confirmed.
Rotraxate hydrochloride is known as a drug which has, as pharmaceutical actions, (1) an action of increasing the blood flow in the gastric mucous membrane and (2) an action of promoting the secretion of bicarbonate ion in the gastric mucous membrane and exhibits an anti-ulcer action that reinforces the function of protection of the gastric mucous membrane (see Japanese Examined Patent Publication (Kokoku) No.
60-36418).
Cetraxate hydrochloride is a drug which is used clinically for adaptation symptoms such as (1) lesions in the gastric mucous membrane (sores, bleeding, reddening, edema) due to the following ailments: acute gastritis and the acute exacerbated phase of chronic gastritis and (2) stomach ulcers (Nihon Iyakuhinshu 1993, p. 581, Yakuji Jihosha).
Mafenide acetate has been known in the past as an .. ~ -antibacterial agent and is effective for infection of wound surfaces by bacteria at the time of burns (Nihon Yakuhin Yoran, 5th edition, p. 1140, Yakuji Jihosha).
Dopamine hydrochloride is a drug which is used clinically for adaptation symptoms such as (1) acute circulatory insufficiency (cardiogenic shock, hemorraghic shock) and (2) acute circulatory insufficiency conditions (Nihon Iyakuhinshu 1993, p. 772, Yakuji Jihosha).
However, no method of use for improving the absorption by nasal powders of peptide proteinaceous drugs has been known for tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention. Further, they are not included in the protease inhibitors mentioned in the patent relating to nasal preparations of Illum et al.
Tranexamic acid suppresses the enzymatic degradation of the peptide proteinaceous drug in the human nasal cavity, so it could be guessed that there is plasmin present in the human nasal cavity and that the plasmin cleaves down the peptide proteinaceous drug, but in the present invention the plasmin activity is low and, also, no effect of promoting nasal absorption was observed in by the E-amino caproic acid, which is a kind of plasmin inhibitor, so the possibility of plasmin playing a major part in the degradation of the peptide proteinaceous drug is denied.
Further, a trypsin-like enzyme is present in the human nasal cavity. The peptide proteinaceous drug administered in the nasal cavity is mainly cleaved by this enzyme. It is possible to improve the nasal absorbency of peptide proteinaceous drugs by administering a trypsin inhibitor in the human nasal cavity at the same time. However, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention have no trypsin 2145,302 ~-- -inhibiting activity, but maintain a higher effect that the effect of promotion of the rate of nasal absorption of a trypsin inhibitor.
In other words, a trypsin-like enzyme exists in the human nasal cavity and the peptide proteinaceous drug administered in the nasal cavity is mainly broken down by that enzyme, but it is believed that the enzyme is restrained more effectively than a trypsin inhibitor by the compound of the present invention, such as tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, etc.
Accordingly, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention can improve the stability of peptide proteinaceous drugs in the human nasal cavity and, accordingly, by administering them together with peptide proteinaceous drugs in the nasal cavity, can improve the nasal absorbency of the peptide proteinaceous drugs.
The tranexamic acid used herein means trans-4-(aminomethyl) cyclohexane carboxylic acid, but in the present invention use may also be made of the cis-forin, namely, cis-4-(aminomethyl) cyclohexane carboxylic acid.
Further, the rotraxate hydrochloride means a hydrochloride of 3-((p-(trans-4-aminomethylcyclohexyl-carbonyl)phenyl)) propionic acid, but in the present invention, use may also be made of the cis-form, namely, a hydrochloride of 3-(p-(cis-4-aminomethylcyclohexyl-carbonyl)phenyl) propionic acid and also other pharmaceutically allowable salts.
Further, the cetraxate hydrochloride means a hydrochloride of trans-(4-aminomethyl) cyclohexane carboxylic acid p-(2-carboxyethyl)phenyl ester, but in .35 the present invention, use may also be made of the cis-form, namely, cis-(4-aminomethyl) cyclohexane carboxylic acid p-(2-carboxy ethyl)phenyl ester and also ~~.., -other different pharmaceutically allowable salts.
Further, the mafenide acetate means an acetate of 4-(aminomethyl) benzenesulfamine, but in the present invention, use may also be made of other pharmaceutically allowable salts.
Further, the dopamine hydrochloride means a hydrochloride of 4-(2-aminoethyl)-1,2 benzenediol, but in the present invention, use may also be made of other pharmaceutically allowable salts.
The salt of the compound of the above formula (I) or (II) of the present invention means, for example, an acid addition salt, metal salt, or other pharmaceutically allowable salt. As a metal salt, mention may be made of a sodium salt, potassium salt, and other alkali metal salt.
It should be noted that the acid of the acid addition salt is not limited so long as it gives a pharmaceutically allowable acid addition salt. For example, mention may be made of hydrochloric acid, sulfuric acid, phosphoric acid, and other inorganic acids and for example acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and other organic acids, etc.
In particular, preferable mention may be made of hydrochloric acid, acetic acid, etc.
In the present invention, as the peptide proteinaceous drug, mention may be made of at least one type of peptide proteinaceous drug selected from the group comprising calcitonins, somatostatin (GIF) and its derivatives, parathyroid hormones (PTH), substance P, platelet derived growth factors (PDGF), galanin, gastrin, neurokinins, interleukins, neurotensin, endo serine, growth hormone-releasing hormone (GHRH) and its derivatives, growth hormone releasing factor (GRF), luteinizing hormone-releasing hormone (LHRH) and its derivative, enkephalin and its derivatives, secretin, bradykinin and its derivatives, adrenocorticotrophic hormone (ACTH) and its derivatives, insulins, glucagon, insulin growth factor (IGF), calcitonin gene related peptide (CGRP), vasopressin and its derivatives, atrial natrium peptide (ANP), erythropoietin, granulocyte colony stimuli factor (G-CSF), and macrophage colony stimuli factor (M-CSF).
Among these, as preferable peptide proteinaceous drugs of the present invention, mention may be made of calcitonin, somatostatin (GIF), growth hormone releasing hormone (GHRH), luteinizing hormone-releasing hormone (LHRH), parathyroid hormone (PTH), or their derivatives.
Among these drugs, calcitonin is a peptide hormone which regulates the metabolism of calcium in the body. It works to obstruct the absorption of calcium in the bones and to cause the reabsorption of calcium released from the kidneys. There are known salmon calcitonin, eel calcitonin, human calcitonin, pig calcitonin, chicken calcitonin, bovine calcitonin, sheep calcitonin, rat calcitonin, etc. In the present invention, use may be made of the derivatives of these calcitonins, for examle, elcatonin and other synthetic calcitonin and genetically engineered calcitonin.
Somatostatin (GIF) is a peptide comprised of 14 amino acid residues which act on the pituitary of vertebrates to suppress the release of GH and TSH and PRL
and suppress secretion of gastrin, motilin, secretin, digestive enzymes, gastric acids, etc. in the gastropancreatic system. There are known human, rat, sheep, dove, angler, and pig types. As derivatives of somatostatin, there are known for example ones like octoreotide acetate and other synthetic somatostatins wherein part of the amino acids are substituted with the D-form and several amino acids are removed to give 6 to 7 amino acid residues. In the present invention, each of these may also be used.
The luteinizing hormone-releasing hormone (LHRH) is a peptide.which acts on the GTH cells of the anterior pituitary of vertebrates to cause the release of LH and FSH. Human, pig, chicken, salmon, and eel types are _2145302 known. As the derivatives, there are known for example [D-Ser(t-Bu)6, des-Gly10 ethylamide] LHRH, [D-Ala-3(2-Naphtyl)6] LHRH, [D-Leu6, des-Gly10 ethylamide]
LHRH, [D-Ser(t-Bu)6, aza-Gly10] LHRH, [N-Ac-D-Nal(2)1, DpFPhe2, D-Pal ( 3) 3, Lys ( Nic ) 5, D-Lys ( Nic ) 6, Lys ( iPr ) 8, D-Ala10] LHRH, and other synthetic LHRH and others with the 6-position Gly substituted with a D-form and others with the C-terminal glysine-amide substituted with alkylamine.
The growth hormone releasing hormone (GHRH) is a peptide which is comprised of 43 to 44 amino acid residues which act on the anterior pituitary of mammals and cause the release of growth hormones (GH). There are known human, rat, bovine, sheep, and pig types. As the derivatives, there are known ones with the C-terminal taken and made (1-29)-NH2 etc. In the present invention, each of these may also be used.
Parathyroid hormone (PTH) is a peptide which is comprised of 84 amino acid residues which act on bone and kidney and promote reabsorption of Ca2+. As its derivatives, there are known PTH1_34NH2, which is comprised of 1 to 34 amino acid residues of the N terminal etc. In the present invention, each of these may also be used.
As the combination of the absorption accelerant of the present invention and the peptide proteinaceous drug, mention may be made of the absorption accelerant having the above formula (I) or expressed by the formula (II) and a peptide proteinaceous drug. Among these, as preferable combinations, mention may be made of (1) an absorption accelerant of tranexamic acid, rotraxate hydrochloride or cetraxate hydrochloride and, in this case, a peptide proteinaceous drug of, for example, the above illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, growth hormone acceleration hormones, and their derivatives, (2) an absorption accelerant of mafenide or _2145302 its pharmaceutically allowable acid addition salts, in particular, mafenide acetate, and, in this case, a peptide proteinaceous drug of, for example, the above illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, and their derivatives, and (3) an absorption accelerant of dopamine or its pharmaceutically allowable acid addition salts, in particular, dopamic hydrochloride, and, in this case, a peptide proteinaceous drug of, for example, the above-illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, and their derivatives.
The amount of the peptide proteinaceous drug in the present invention is the therapeutically effective amount. The amount is specific to the different types of peptide proteinaceous drug. The therapeutically effective amount is usually preferably the same amount 1 to 20 times the amount of the peptide proteinaceous drug administered by injection, more preferably 2 to 10 times the amount.
On the other hand, the amount of the absorption accelerant of the present invention is preferably approximately 0.1-10 parts by weight based on 1 part by weight of the therapeutically effective amount of the peptide proteinaceous drug, more preferably approximately 1 to 5 parts by weight, still more preferably 1 to 3 parts by weight. The amounts and ratio in the case of mixing two or more types of absorption accelerants are not particularly limited, but the total amount is preferably in this range.
The peptide proteinaceous drug nasal powder of the present invention is produced by mixing one or more types of a fine powder peptide proteinaceous drug and the absorption accelerant of the present invention, for example, a water absorbing and water-insoluble base. The mixing is performed using a mortar, high speed mixer, or other usual mixer. The water-absorbing and _2145302 water-insoluble base spoken of here means something which has absorbency and insolubility on human nasal mucous membrane or in an environment close to that, that is, with respect to water of a pH of about 7.4 and a temperature of about 36 C to about 37 C.
As preferable specific examples, mention may be made of water-absorbing and water-insoluble cellulose such as microcrystalline cellulose, a-cellulose, cross-linked sodium carboxymethylcellulose, and their derivatives;
water-absorbing and water-insoluble hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin and their derivatives;
water-absorbing and water-insoluble gum such as arabia gum, tragacanth gum, glucomannan and their derivatives;
and cross-linked vinyl polymers such as polyvinylpolypyridone, cross-linked polyacrylic acid and its salt, cross-linked polyvinyl alcohol, polyhydroxyethylmethacrylate and their derivatives. Among these, water-absorbing and water-insoluble cellulose is preferable, in particular, microcrystalline cellulose and its derivative are desirable.
It is also possible to add to this powder, in addition to the one or more types of peptide proteinaceous drugs, the absorption accelerant of the present invention, and above-mentioned substrate, according to requirement, a known lubricant, preservative, antiseptic, deodorant, etc.
As a lubricant, for example, mention may be made of talc, stearic acid and its salts, etc.; as a colorant, for example, mention may be made of copper chlorophyll, J3-carotene, red No. 2, blue No. 1, etc.; as a preservative, for example, mention may be made of stearic acid, ascorbic acid stearate, etc.; as an antiseptic, for example, mention may be made of benzylkonium chloride and other quaternary ammonium compounds, paraoxybenzoic acid esters, phenols, chlorobutanol, etc.; and as deodorant, mention may be made for example of menthol, citrus _2145302 fragrances, etc.
The peptide proteinaceous drug nasal powder of the present invention is usually administered in the nasal cavity by the following method. That is, a capsule filled with the powder to set for example in an exclusive spray apparatus possessing a needle, the needle is made to penetrate it to make fine holes at the top and bottom of the capsule, then air is fed by a rubber ball etc. to make the powder spray out.
EXAMPLES
The present invention will now be explained in more detail in accordance with the Reference Experiments and Examples, but of course the present invention is not limited to these Examples.
Reference Experiment 1 (1) A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml protein. To 0.5 ml portions of this homogenate were added 0.5 ml portions of an aqueous solution of salmon calcitonin (0.1 mg/ml). The results were incubated at 37 C, then the degradation fragments of the salmon calcitonin in the reaction liquid were separated by HPLC (L-6200 series (made by Hitachi, Ltd.) by 100% H20 from 0 to 5 minutes, 100% to 50% H20 and 0 to 50% acetonitrile from 5 to 55 minutes). The amino acid sequences of the separated fragments were determined by an amino-acid sequencer (made by Applied Biosystems). The first fragment of salmon calcitonin in human nasal mucosal homogenate are shown to Table 1.
Table 1: Degradation Fragments in Human Nasal Mucosal Membrane Homogenate Salmon calcitonin Cys-Ser-Asn-Leu-Ser-Thr-Cys-fragment 1 Val-Leu-Gly-Lys Salmon calcitonin Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-fragment 2 Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 As shown in Table 1, the C end side of Lys of the peptide proteinaceous drug is first cleaved in a human nasal mucosal homogenate. From this, it is guessed that the protease which first cleaves the peptide proteinaceous drug in the human nasal cavity is a trypsin-like enzyme.
A refined trypsin (made by Wako Pure Chemical Industry) was used, instead of the human nasal mucosal homogenate solution, in the same procedures followed as in (1) to separate the degradation fragments of salmon calcitonin in the reaction liquid by HPLC. In the same way as (1), the amino acid sequence was determined by an amino-acid sequencer. The results are shown in Table 2.
Table 2: Salmon Calcitonin Degradation Fraqments by Trypsin Fragment 1 Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys Fragment 1 Leu-Ser-Gln-Glu-Leu-His-Lys Fragment 1 Leu-Gln-Thr-Tyr-Pro-Arg Fragment 1 Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-As shown in Table 2, the degradation fragments of salmon calcitonin caused by refined trypsin are different from the degradation fragments of salmon calcitonin of Table 1. From this, it is guessed that the trypsin-like enzyme present in the human nasal cavity is not trypsin itself.
Reference Experiment 2 A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml of protein. Next, synthesis substrates corresponding to the various proteases shown in Table 1 were added to 0.5 ml portions of the homogenate solution to give 0.1 mM concentrations. The results were incubated at 37 C. The amounts of the substrates remaining after a predetermined time were measured by HPLC to find the amounts of substrates cleaved and find the activity of the various proteases.
The results are shown in Table 3.
Table 3: Activity of Protease in Human Nasal Mucosal Homogenate Synthesized substrate Corresponding Activity protease (nM/h/mg protein) Boc-Gln-Ala-Arg-MCA Trypsin 525 Boc-Val-Pro-Arg-MCA a-Thrombin 269 Boc-Phe-Ser-Arg-MCA Trypsin 250 Pro-Phe-Arg-MCA Kallikrein 85 Suc-Ala-Ala-Pro-Phe-MCA Chymotrypsin 24 Boc-Glu-Lys-Lys-MCA Plasmin 14 Suc-Ala-Ala-Ala-MCA Elastase 3 Bz-Arg-MCA Trypsin 1 In the synthesis substrates, Boc means a t-Butyloxycarbonyl group, Suc means a Succinyl group, Bz means a Benzyl group, and MCA means 4-Methyl-Coumaryl-7-Amide.
As shown in Table 3, a trypsin-like enzyme has a relatively high activity in human nasal mucosal homogenate, while plasmin has a considerably low activity. However, there were some substrates corresponding to trypsin (in Table 3, Bz-Arg-MCA) which do not cleave much at all. Also, it became clear that the enzyme present in the human nasal mucosal homogenate is not trypsin itself. That is, it is guessed that in the human nasal cavity, peptide proteinaceous drugs are mainly cleaved down by enzymes which are not trypsin, but have trypsin-like activity.
Reference Experiment 3 A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml of protein. Next, 0.25 ml portions of aqueous solutions (72 mM) of the different peptide proteinaceous drugs were added to 0.5 ml portions of the homogenate solution, 0.01 ml portions of aqueous solutions (72M) of different enzyme inhibitors or absorption accelerants of the present invention were added, and the results were incubated at 37 C. The amounts of the peptide proteinaceous drug not yet cleaved after a predetermined time were measured by HPLC to find the amounts of decomposition. The inhibition rates were calculated by the following formula. The results are shown in Table 4.
Inhibition rate (A-B)/A x 100 A: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor or absorption accelerant of present invention is not added to homogenate B: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor or absorption accelerant of present invention is added to homogenate E-ACA: E-Amino caproic acid SCT: Salmon calcitonin INS: Insulin GIF: Somatostatin ACTH: Adrenocorticotropic hormone PTH: Parathyroid hormone CGRP: Calcitonin gene related peptide GLU: Glucogon PDGF: Platelet-derived growth factor S.p: Substance P
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As shown in Table 4, it is clear that by including a trypsin inhibitor, the degradation of the peptide proteinaceous drug in the human nasal mucosal homogenate is obstructed. More surprisingly, it became clear that tranexamic acid, which is not a trypsin inhibitor, and other compounds of the present invention which are not trypsin inhibitors and are also not recognized as enzyme inhibitors, such as cyclohexane methylamine, cetraxate hydrochloride, rotraxate hydrochloride, benzylamine, p-aminomethyl benzoic acid, mafenide acetate, dopamine hydrochloride, etc. have a function of inhibiting the degradation of peptide proteinaceous drugs higher than the trypsin inhibitors of aprotinin and gabexate mesylate (Gabexate). This function is not observed in 6-amino caproic acid (E-ACA), so it is clear that it is not an inhibition function of plasmin. In other words, it is guessed that the enzymes which cleave peptide proteinaceous drugs in human nasal cavities are trypsin-like enzymes having the characteristic of being remarkably restrained in activity by compounds of the present invention like tranexamic acid, cyclohexane methylamine, rotraxate hydrochloride, cetraxate hydrochloride, benzylamine, p-aminomethyl benzoic acid, mafenide acetate, and dopamine hydrochloride.
Example 1 Salmon calcitonin in an amount of 40 g, tranexamic acid 40 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added calcitonin nasal powder.
The powder was weighed to give 100 IU (20 g) of calcitonin, was packed in No. 2 capsules, then was administered to the right nasal cavities of three normal human volunteers by a Publizer (registered trademark, Teijin). After administration, 5 ml of blood was taken from a vein in the forearm every certain period and the concentration of salmon calcitonin in the plasma was measured by the RIA method. The results are shown in Fig.
1 by the time curve of the concentration of salmon calcitonin in the plasma.
Control Example 1 The same procedure was followed as in Example 1, except that 40 g of tranexamic acid was not added, to prepare a tranexamic acid-free calcitonin nasal powder, the powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together in Fig. 1.
Control Example 2 The same procedure was followed as in Example 1, except that use was made of 0.4 mg of aprotinin instead of the 40 g of tranexamic acid in Example 1, to prepare an aprotinin-added calcitonin nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together in Fig. 1.
Example 2 Somatorein acetate (GHRH) in an amount of 2.0 mg, tranexam3.c acid 1.0 mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added GHRH nasal powder. The powder was weighed to give a 1.0 mg amount of GHRH, was packed in No. 2 capsules, and was administered to the right nasal cavities of three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of growth hormone (GH) in the plasma was measured. The results are shown together in Fig. 2 by the time curve of the concentration of GH in the plasma.
Control Example 3 The same procedure was followed as in Example 2, except that 1.0 mg of tranexamic acid was not added, to prepare a tranexamic acid-free GHRH nasal powder, the powder was weighed to give 1.0 mg of GHRH and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 2, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 2.
Control Example 4 The same procedure was followed as in Example 2, except that use was made of 2.0 mg of gabexate mesylate instead of 1.0 mg of tranexamic acid, to prepare a gabexate mesylate-added GHRH nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 2, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 2.
Example 3 Deslorelin (LHRH derivative) in an amount of 0.2 mg, tranexamic acid 0.2 mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added LHRH derivative nasal powder. The powder was weighed to give 1.0 mg of the LHRH
derivative, was packed in No. 2 capsules, then was administered to the right nasal cavities of three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of leuteinizing hormone (LH) in the plasma was measured. The results are shown in Fig. 3 by the time curve of the LH concentration in the plasma.
Control Example 5 The same procedure was followed as in Example 3, except that 0.2 mg of tranexamic acid was not added, to prepare a tranexamic acid-free LHRH derivative nasal powder, the powder was weighed to give 1.0 mg of LHRH
derivative and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 3, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 3.
Control Example 6 The same procedure was followed as in Example 3, except that use was made of 0.4 mg of aprotinin instead of 0.2 mg of tranexamic acid, to prepare an aprotinin-added LHRH derivative nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 3, then after a certain time the concentration of LH in the plasma was measured. The results are shown in Fig. 3.
Example 4 Salmon calcitonin in an amount of 40 g, rotraxate hydrochloride 40 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar and mix to prepare a rotraxate hydrochloride-added calcitonin nasal powder. The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered in the right nasal cavity of three normal human volunteers by a Publizer (registered trademark, Teijin). After administration, 5 ml of blood was taken from a vein in the forearm every certain period and the concentration of salmon calcitonin in the plasma _ was measured by the RIA method. The results are shown in Fig. 4 by the time curve of the concentration of salmon calcitonin in the plasma together with the results of Comparative Examples 1 and 2.
Example 5 Salmon calcitonin in an amount of 40 g, mafenide acetate 60 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a mafenide acetate-added calcitonin nasal powder.
The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered in the right nasal cavity of three normal human volunteers by a Publizer (registered trademark).
After administration, 5 ml of blood was taken from a vein in the forearm every certain period of 5 minutes, 15 minutes, 30 minutes, and 60 minutes, and the concentration of salmon calcitonin in the plasma was measured by the RIA method. The results are shown in Fig.
5 by the time curve of the concentration of salmon calcitonin in the plasma.
Example 6 The same procedure was followed as in Example 5, except that use was made of 50 g of dopamine hydrochloride instead of 60 g of mafenide acetate, to prepare a dopamine hydrochloride-added calcitonin nasal powder. The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 5, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together with the results of the above-mentioned Comparative Examples 1 and 2 in Fig. 5.
INDUSTRIAL APPLICABILITY
According to the present invention, there is provided a peptide proteinaceous drug nasal powder composition which is improved in absorbency and a peptide _2145302 proteinaceous drug nasal powder composition which is improved in absorbency and safe to the body.
Peptide Proteinaceous Drug Nasal Powder Composition TECHNICAL FIELD
The present invention relates to a peptide proteinaceous drug nasal powder composition having an improved absorbency. More specifically, it relates to a peptide proteinaceous drug nasal powder composition, which is improved in absorption from the mucous membrane of the nasal cavity to the blood stream of the entire body by suppression of the decomposition of the peptide proteinaceous drug administered to the nasal cavity by an absorption accelerant having specified groups.
BACKGROUND ART
Along with the progress in biotechnology in recent years, there have been a succession of discoveries of peptide roteinaceous compounds having physiological activity. Production of these compounds has become easy as well. Many of these peptide proteinaceous drugs are used only as injections due to the low level of their stability and absorbency. However, these drugs are preferably administered in multiple dosages for therapeutic reasons. Administration by injection in this case places a burden on the patient due to the pain to the patient and the need for visiting a hospital.
Therefore, other various methods of administration have been examined as non-invasive methods of administration of peptide proteinaceous drugs to take the place of injections, for example, the method of rectal administration by suppositories (J. Pharma., 33 334 (1981)), bronchial administration (Diabetes 20 552 (1971)), instillation administration (Abstracts of Diabetes Society 237 (1964)), etc. All of these methods, however, are hard to commercialize due to the difficulties that higher dosages are required than with injections and the absorption tends to fluctuate.
On the other hand, the nasal cavity has a well '~- 2145302 developed system of blood vessels in the mesothelium layer and is able to absorb a drug quickly and with little variation. Due to these advantages, the nasal administration method has come into attention. At the present time, however, sufficient absorption cannot be obtained, and therefore, various studies are under way to raise the absorbency.
For example, Nolte et al. (Hormone Metabolic Research 22, 170-174, 1990), Moses (Pharmaceutisch Week-blad-Scientific Edition 10, 45-46, 1988), Bruce et al. (Diabetic Medicine 8, 366-370,1991), etc. report on nasal administration of insulin containing sodium glycocholate or sodium taurofusidate as absorption accelerants. These preparations containing absorption accelerants, however, have problems with irritation to the nasal mucous membrane, and therefore, have not been commercialized.
As the major causes for the low absorbency of a peptide proteinaceous drug from the nasal mucous membrane, Illum (Trends Biotechnol 9, 284-289, 1991), W.A. Lee (Biopharm. Manuf. 1, 30-37, 1988), Edman (Advanced Drug Delivery Reviews 8, 165-177, 1992), etc.
have mentioned the low level of drug permeability into the mucous membrane, the elimination of the drug by ciliary movement, and the degradation of the drug by the protease in the nasal cavity.
Among these, as a major discovery relating to the protease in the nasal cavity, 0' Hagan et al. (Pharm.
Res. 7, 772 (1990)), Hussain et al. (Pharm. Res. 6, 186 (1989)), showed by animal experiments using rats and sheep that the nasal absorption of insulin, growth hormone, enkephalin, and other peptide proteinaceous drugs is improved by administration together with amastatin, bestatin, a-aminoboronic acid, or other aminopeptidase inhibitors.
Further, Illum et al. (Japanese National Disclosure (Kohyo) No. 2-503915) mentioned that effective protease inhibitors for nasal preparations in studies of rats, rabbits, and sheep were actinonin, amastatin, bestatin, chloroacetyl-HO-Leu-Ala-Gly-NH2, diprotin A and B, evelactone A and B, E- 64, H-(tBu)-Phe-Pro-OH, kallikrein inhibitor I, chymotrypsin inhibitor I, trypsin inhibitor III - 0, leupeptin, pepstatin, phosphoramidone, aprotinin, chymostatin, and benzamidine.
Further, Morimoto et al. (111 and 112 Ann. Meetings of JPN Pharm, Soc.) showed by by animal experiments using rats that the nasal absorbency of salmon calcitonin was improved by administering it with aprotinin, TAME (tosyl arginine methyl ester), which was a synthetic substrate of trypsin, or other trypsin inhibitors.
Further, the present inventors confirmed by animal experiments using rabbits that in the nasal cavity of rabbits, salmon calcitonin, LHRH, insulin, and other peptide proteinaceous drugs were cleaved at the C
terminal of the Leu in their primary structures and that the nasal absorbency of these is improved by administering them with a chymotrypsin inhibitor (for example, see Japanese Patent Application No. 5-130993 i.e., Japanese Unexamined Patent Publication No. 6-321804.
These findings, however, were all based on animal experiments using rats, sheep, and rabbits and the significance for humans is unclear. Accordingly, at the present time, it is not clear if the methods for improving the nasal absorbency of peptide proteinaceous drugs in rats, sheep, rabbits, and other animals would be effective for humans.
DISCLOSURE OF INVENTION
Accordingly, the present invention provides a peptide proteinaceous drug nasal powder composition which, by combined use of a protease inhibitor, suppresses the degradation of the peptide proteinaceous drug in the human nasal cavity by the action of the enzyme, is improved in the nasal absorbency, and is safe to the body.
In accordance with the present invention, there is provided a peptide proteinaceous drug nasal powder composition comprising (i) an absorption accelerant comprising a compound, or its salt, having in its molecule a group expressed by the formula (I):
4 ( I ) NH2- (CH2)~ 0 (wherein, - indicates a cyclohexane ring or a benzene ring which may be substituted at least at one of its 3-position, 4-position, and 5-position and n is an integer of 1 to 3) and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
In accordance with one embodiment of the present invention there is provided a peptide proteinaceous drug nasal powder composition comprising (i) an absorption accelerant comprising a compound, or its salt, having in the compound molecule a group expressed by the formula (II):
RI
; '.
NHZ - (CI-i2)n RZ
(II) ; ', wherein represents a cyclohexane ring or a benzene ring; n is an integer of 1 or 2; R', R2 and RI are, independently, a member selected from the group consisting - 4a -of a hydrogen atom -COOR, -COR, -OR', and -SOzNH2, which may be substituted; provided that at least one of R1, R' or R3 is a hydrogen atom; R represents a hydrogen atom, a C1-Ce lower alkyl group which may be substituted, or -( U}- CH2CH2COOR' , R' represents a hydrogen atom, a C1-C6 loweralkyl group which may be substituted, a phenyl group which may be substituted, or a C7-C8 aralkyl group which may be substituted, and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will now be explained in further detail with reference to the drawings; wherein:
Figure 1 is a graph showing the changes along with time of the concentration of salmon calcitonin in the plasma in normal human volunteers after administration of a calcitonin nasal powder composition;
Figure 2 is a graph showing the changes along with time of the concentration of GH in the plasma in normal human volunteers after administration of a GHRH nasal powder composition;
Figure 3 is a graph showing the changes along with time of the concentration of LH in the plasma in normal human volunteers after administration of an LHRH nasal powder composition;
Figure 4 is a graph showing the changes along with time of the concentration of salmon calcitonin in the plasma in normal human volunteers in Example 4 after ~, -administration of a calcitonin nasal powder composition;
and Figure 5 shows the concentration of calcitonin in the plasma in the case of administration of nasal preparations of the present invention in Examples 5 and 6 and nasal preparations in Control Examples 1 and 2.
BEST MODE FOR CARRYING OUT THE INVENTION
As mentioned above, the present inventors found that a compound having the specific formula (I) suppressed the degradation of peptide proteinaceous drugs in the human nasal cavity and improves the nasal absorbency.
It should be noted that, as is clear from the later Reference Experiments and Examples, the compound having the above-mentioned formula (I), that is, the absorption accelerant for providing a peptide proteinaceous drug preparation which suppresses the degradation of peptide proteinaceous drug in the human nasal cavity by the action of the protease and improves the nasal absorbency, as aimed at by the present invention, may be said to be a compound where the aminomethyl group, aminoethyl group, and aminopropyl group have attached to them a cyclohexane ring or benzene ring that cannot cover these groups spatially due to the intermolecular electrostatic interaction or rigidity etc. Accordingly, also included in the absorption accelerant of the present invention are compounds in which the substituents and cyclohexane and benzene are substituted by other substituents, for example, chain (straight chain, branched) or cyclic saturated or unsaturated hydrocarbon groups etc. to the extent to which it is naturally assumed that these groups will not be covered spatially due to the intermolecular electrostatic interaction or rigidity etc.
That is, the compound of formula (I) has a NH2-(CH2)a-group. It is essential that this is bonded together with a cyclohexane ring or benzene ring. With just this structure, the cyclohexane ring or benzene ring ~. -may have a substituent at the 3-, 4-, and/or 5-position three-dimensionally separated from the NHZ-(CH2)a-group.
The substituent is not particularly limited so long as it is a group which is stable as a preparation in the case of being made a powder and which poses no safety problem in terms of irritation etc. when administered to a human patient. More specifically, the compound having the group of the structure of formula (I) may be expressed by the following general formula (II):
R' NH:-(CH:). R' (II) R' wherein, n is an integer of 1 to 3, preferably 1 to 2, and R1, RZ, and R3 are, independently, a group selected from a hydrogen atom, phosphoric acid group, cyano group, COOR, COR, OR', S(0)PR', NR'R", carbamoyl group, S02NHZ, and substitutable C1-C20 hydrocarbon group, wherein R
represents a hydrogen atom; C1-C6 lower alkyl group which may be substituted; or - CHZCHZCOOR', R' and R"
epresent, independently, a hydrogen atom; C1-C6lower alkyl group which may be substituted, phenyl group which may be substituted, or C7-C8 aralkyl group which may be substituted, and p is an integer of 0 to 3.
In these Rl to R3, as the C1-C6 lower alkyl group, mention may be made of a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, and other straight chain or branched chain or cyclic alkyl groups. Among these, a methyl group, ethyl group, n-butyl group, and other C1-C4 lower alkyl groups may be mentioned as being preferable. Further, as the C7-C8 aralkyl group, mention may be made of a benzyl group and phenylethyl group.
_2145302 Further, the C1-C20 hydrocarbon group means a saturated or unsaturated chain (straight chain or branched) or cyclic hydrocarbon group. For example, mention may be made of those similar to those illustrated as the C1-C6lower alkyl group and those which, when unsaturated, have one or more double bonds and/or triple bounds, such as a heptyl group, decyl group, eicosyl group, 2,2-dimethyloctyl group, cyclohexylbutyl group, propenyl group, isopentenyl group, 8-heptadecenyl group, and 8,11-heptadecadienyl group. As the C1-C20 hydrocarbon group, preferably, mention may be made of a Ci-C15 hydrocarbon group, more preferably a C1-Clo hydrocarbon group.
As a specific example of the COOR of the R' to R3, mention may be made of a carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, hexyloxycarbonyl group, and - C00 CHZCH2COOR' and as a specific example of the COR, mention may be made of formyl group, acetyl group, propionyl group, and CO CH2CH2COOR'.
Further, as specific examples of the S(0)PR', mention may be made of a thiol group, sulfenic acid group, sulfinic acid group, sulfonic acid group, methylthiol group, isopropyl thiol group, isopropyl sulfinyl group, isopropyl sulfonyl group, pentyl sulfonyl group, phenyl thiol group, phenyl sulfonyl group, etc.
Further, as specific examples of NR'R", mention may be made of an amine group, dimethyl amine group, diethyl amine group, benzyl amine group, phenethyl amine group, etc.
Further, as specific examples of the OR', mention may be made of a hydroxyl group, methoxyl group, ethoxyl group, (n-, i-) propoxyl group, (n-, i-, s-, t-) butoxyl group, hexyloxyl group, cyclopropylmethyloxyl group, phenyloxyl group, phenethylloxyl group, etc.
_2145302 The R' to R3 of the present invention may, when having a C1-C20 hydrocarbon group; C1-C6 lower alkyl group, phenyl group, or C7-C8 aralkyl group, further have substituents at these groups. As such substituents, mention may be made of the phosphoric acid group, cyano group, COOR, COR, OR', S(0)pR', NR'R", carbamoyl group, and SOZNH2 exemplified as R' to R3.
As the absorption accelerant of the present invention, mention may be made of the compounds in formula (I) or (II), wherein n = 1 or 2 mentioned as preferable.
As the substituent on the cyclohexane ring or benzene ring in the above-mentioned formula (I) or (II), mention may be made of a substituent selected from COOR, COR, OR', SO2NH2 and a C1-Cio hydrocarbon group among those illustrated as R1 to R3.
In particular, in the above-mentioned formula (I) or (II), when the cyclic structure is a cyclohexane ring and n =1, preferable mention may be made of a compound wherein the substituent is a group selected from among the group comprising a hydrogen atom, COOR, and COR. In particular, preferable mention may be made of a group selected from the group comprising a hydrogen atom, carboxyl group, C00 _~a CH2CH2COOH, and CO -4a CH2CH2COOH
In this case, specific mention may be made of the case where as the substituents as R' to R3, R1 to R3 are hydrogen atoms or R1 and R3 are hydrogen atoms and R 2 is a group other than a hydrogen atom.
Further, when the cyclic structure is a benzene ring and n = 1 or 2 in the above-mentioned formula (I) or (II), preferable mention may be made of a compound wherein the substituent is a group selected from the group comprising a hydrogen atom, SOZNH2, and OR', in particular, mention may be made of the case where n = 1 _2145302 and the substituent is a group selected from a hydrogen atom, carboxyl group, and SO2NH2(sulfamine) group or n 2 and the substituent is a hydrogen atom or hydroxyl group. In this case, specific mention may be made of the case where as the substituents as R1 to R3, when n = 1, R1 to R3 are hydrogen atoms or R1 and R3 are hydrogen atoms and R 2 is a carboxyl group or SOZNHZ group or, when n = 2, R1 is a hydrogen atom and R 2 and R3 are hydroxyl groups.
As further preferable examples of the compounds having the formula (I), mention may be made for example of cyclohexane methylamine, benzylamine, p- aminomethyl benzoic acid, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and their derivatives and acid addition salts and other salts.
Tranexamic acid has been known as a hemostyptic and is used at the time of abnormal bleeding caused by systemic hyperfibrinolysis. Its safety in the body has already been confirmed.
Rotraxate hydrochloride is known as a drug which has, as pharmaceutical actions, (1) an action of increasing the blood flow in the gastric mucous membrane and (2) an action of promoting the secretion of bicarbonate ion in the gastric mucous membrane and exhibits an anti-ulcer action that reinforces the function of protection of the gastric mucous membrane (see Japanese Examined Patent Publication (Kokoku) No.
60-36418).
Cetraxate hydrochloride is a drug which is used clinically for adaptation symptoms such as (1) lesions in the gastric mucous membrane (sores, bleeding, reddening, edema) due to the following ailments: acute gastritis and the acute exacerbated phase of chronic gastritis and (2) stomach ulcers (Nihon Iyakuhinshu 1993, p. 581, Yakuji Jihosha).
Mafenide acetate has been known in the past as an .. ~ -antibacterial agent and is effective for infection of wound surfaces by bacteria at the time of burns (Nihon Yakuhin Yoran, 5th edition, p. 1140, Yakuji Jihosha).
Dopamine hydrochloride is a drug which is used clinically for adaptation symptoms such as (1) acute circulatory insufficiency (cardiogenic shock, hemorraghic shock) and (2) acute circulatory insufficiency conditions (Nihon Iyakuhinshu 1993, p. 772, Yakuji Jihosha).
However, no method of use for improving the absorption by nasal powders of peptide proteinaceous drugs has been known for tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention. Further, they are not included in the protease inhibitors mentioned in the patent relating to nasal preparations of Illum et al.
Tranexamic acid suppresses the enzymatic degradation of the peptide proteinaceous drug in the human nasal cavity, so it could be guessed that there is plasmin present in the human nasal cavity and that the plasmin cleaves down the peptide proteinaceous drug, but in the present invention the plasmin activity is low and, also, no effect of promoting nasal absorption was observed in by the E-amino caproic acid, which is a kind of plasmin inhibitor, so the possibility of plasmin playing a major part in the degradation of the peptide proteinaceous drug is denied.
Further, a trypsin-like enzyme is present in the human nasal cavity. The peptide proteinaceous drug administered in the nasal cavity is mainly cleaved by this enzyme. It is possible to improve the nasal absorbency of peptide proteinaceous drugs by administering a trypsin inhibitor in the human nasal cavity at the same time. However, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention have no trypsin 2145,302 ~-- -inhibiting activity, but maintain a higher effect that the effect of promotion of the rate of nasal absorption of a trypsin inhibitor.
In other words, a trypsin-like enzyme exists in the human nasal cavity and the peptide proteinaceous drug administered in the nasal cavity is mainly broken down by that enzyme, but it is believed that the enzyme is restrained more effectively than a trypsin inhibitor by the compound of the present invention, such as tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, etc.
Accordingly, tranexamic acid, rotraxate hydrochloride, cetraxate hydrochloride, mafenide acetate, dopamine hydrochloride, and other compounds of the present invention can improve the stability of peptide proteinaceous drugs in the human nasal cavity and, accordingly, by administering them together with peptide proteinaceous drugs in the nasal cavity, can improve the nasal absorbency of the peptide proteinaceous drugs.
The tranexamic acid used herein means trans-4-(aminomethyl) cyclohexane carboxylic acid, but in the present invention use may also be made of the cis-forin, namely, cis-4-(aminomethyl) cyclohexane carboxylic acid.
Further, the rotraxate hydrochloride means a hydrochloride of 3-((p-(trans-4-aminomethylcyclohexyl-carbonyl)phenyl)) propionic acid, but in the present invention, use may also be made of the cis-form, namely, a hydrochloride of 3-(p-(cis-4-aminomethylcyclohexyl-carbonyl)phenyl) propionic acid and also other pharmaceutically allowable salts.
Further, the cetraxate hydrochloride means a hydrochloride of trans-(4-aminomethyl) cyclohexane carboxylic acid p-(2-carboxyethyl)phenyl ester, but in .35 the present invention, use may also be made of the cis-form, namely, cis-(4-aminomethyl) cyclohexane carboxylic acid p-(2-carboxy ethyl)phenyl ester and also ~~.., -other different pharmaceutically allowable salts.
Further, the mafenide acetate means an acetate of 4-(aminomethyl) benzenesulfamine, but in the present invention, use may also be made of other pharmaceutically allowable salts.
Further, the dopamine hydrochloride means a hydrochloride of 4-(2-aminoethyl)-1,2 benzenediol, but in the present invention, use may also be made of other pharmaceutically allowable salts.
The salt of the compound of the above formula (I) or (II) of the present invention means, for example, an acid addition salt, metal salt, or other pharmaceutically allowable salt. As a metal salt, mention may be made of a sodium salt, potassium salt, and other alkali metal salt.
It should be noted that the acid of the acid addition salt is not limited so long as it gives a pharmaceutically allowable acid addition salt. For example, mention may be made of hydrochloric acid, sulfuric acid, phosphoric acid, and other inorganic acids and for example acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and other organic acids, etc.
In particular, preferable mention may be made of hydrochloric acid, acetic acid, etc.
In the present invention, as the peptide proteinaceous drug, mention may be made of at least one type of peptide proteinaceous drug selected from the group comprising calcitonins, somatostatin (GIF) and its derivatives, parathyroid hormones (PTH), substance P, platelet derived growth factors (PDGF), galanin, gastrin, neurokinins, interleukins, neurotensin, endo serine, growth hormone-releasing hormone (GHRH) and its derivatives, growth hormone releasing factor (GRF), luteinizing hormone-releasing hormone (LHRH) and its derivative, enkephalin and its derivatives, secretin, bradykinin and its derivatives, adrenocorticotrophic hormone (ACTH) and its derivatives, insulins, glucagon, insulin growth factor (IGF), calcitonin gene related peptide (CGRP), vasopressin and its derivatives, atrial natrium peptide (ANP), erythropoietin, granulocyte colony stimuli factor (G-CSF), and macrophage colony stimuli factor (M-CSF).
Among these, as preferable peptide proteinaceous drugs of the present invention, mention may be made of calcitonin, somatostatin (GIF), growth hormone releasing hormone (GHRH), luteinizing hormone-releasing hormone (LHRH), parathyroid hormone (PTH), or their derivatives.
Among these drugs, calcitonin is a peptide hormone which regulates the metabolism of calcium in the body. It works to obstruct the absorption of calcium in the bones and to cause the reabsorption of calcium released from the kidneys. There are known salmon calcitonin, eel calcitonin, human calcitonin, pig calcitonin, chicken calcitonin, bovine calcitonin, sheep calcitonin, rat calcitonin, etc. In the present invention, use may be made of the derivatives of these calcitonins, for examle, elcatonin and other synthetic calcitonin and genetically engineered calcitonin.
Somatostatin (GIF) is a peptide comprised of 14 amino acid residues which act on the pituitary of vertebrates to suppress the release of GH and TSH and PRL
and suppress secretion of gastrin, motilin, secretin, digestive enzymes, gastric acids, etc. in the gastropancreatic system. There are known human, rat, sheep, dove, angler, and pig types. As derivatives of somatostatin, there are known for example ones like octoreotide acetate and other synthetic somatostatins wherein part of the amino acids are substituted with the D-form and several amino acids are removed to give 6 to 7 amino acid residues. In the present invention, each of these may also be used.
The luteinizing hormone-releasing hormone (LHRH) is a peptide.which acts on the GTH cells of the anterior pituitary of vertebrates to cause the release of LH and FSH. Human, pig, chicken, salmon, and eel types are _2145302 known. As the derivatives, there are known for example [D-Ser(t-Bu)6, des-Gly10 ethylamide] LHRH, [D-Ala-3(2-Naphtyl)6] LHRH, [D-Leu6, des-Gly10 ethylamide]
LHRH, [D-Ser(t-Bu)6, aza-Gly10] LHRH, [N-Ac-D-Nal(2)1, DpFPhe2, D-Pal ( 3) 3, Lys ( Nic ) 5, D-Lys ( Nic ) 6, Lys ( iPr ) 8, D-Ala10] LHRH, and other synthetic LHRH and others with the 6-position Gly substituted with a D-form and others with the C-terminal glysine-amide substituted with alkylamine.
The growth hormone releasing hormone (GHRH) is a peptide which is comprised of 43 to 44 amino acid residues which act on the anterior pituitary of mammals and cause the release of growth hormones (GH). There are known human, rat, bovine, sheep, and pig types. As the derivatives, there are known ones with the C-terminal taken and made (1-29)-NH2 etc. In the present invention, each of these may also be used.
Parathyroid hormone (PTH) is a peptide which is comprised of 84 amino acid residues which act on bone and kidney and promote reabsorption of Ca2+. As its derivatives, there are known PTH1_34NH2, which is comprised of 1 to 34 amino acid residues of the N terminal etc. In the present invention, each of these may also be used.
As the combination of the absorption accelerant of the present invention and the peptide proteinaceous drug, mention may be made of the absorption accelerant having the above formula (I) or expressed by the formula (II) and a peptide proteinaceous drug. Among these, as preferable combinations, mention may be made of (1) an absorption accelerant of tranexamic acid, rotraxate hydrochloride or cetraxate hydrochloride and, in this case, a peptide proteinaceous drug of, for example, the above illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, growth hormone acceleration hormones, and their derivatives, (2) an absorption accelerant of mafenide or _2145302 its pharmaceutically allowable acid addition salts, in particular, mafenide acetate, and, in this case, a peptide proteinaceous drug of, for example, the above illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, and their derivatives, and (3) an absorption accelerant of dopamine or its pharmaceutically allowable acid addition salts, in particular, dopamic hydrochloride, and, in this case, a peptide proteinaceous drug of, for example, the above-illustrated salmon calcitonin and other calcitonins, human somatostatin and other somatostatins, and their derivatives.
The amount of the peptide proteinaceous drug in the present invention is the therapeutically effective amount. The amount is specific to the different types of peptide proteinaceous drug. The therapeutically effective amount is usually preferably the same amount 1 to 20 times the amount of the peptide proteinaceous drug administered by injection, more preferably 2 to 10 times the amount.
On the other hand, the amount of the absorption accelerant of the present invention is preferably approximately 0.1-10 parts by weight based on 1 part by weight of the therapeutically effective amount of the peptide proteinaceous drug, more preferably approximately 1 to 5 parts by weight, still more preferably 1 to 3 parts by weight. The amounts and ratio in the case of mixing two or more types of absorption accelerants are not particularly limited, but the total amount is preferably in this range.
The peptide proteinaceous drug nasal powder of the present invention is produced by mixing one or more types of a fine powder peptide proteinaceous drug and the absorption accelerant of the present invention, for example, a water absorbing and water-insoluble base. The mixing is performed using a mortar, high speed mixer, or other usual mixer. The water-absorbing and _2145302 water-insoluble base spoken of here means something which has absorbency and insolubility on human nasal mucous membrane or in an environment close to that, that is, with respect to water of a pH of about 7.4 and a temperature of about 36 C to about 37 C.
As preferable specific examples, mention may be made of water-absorbing and water-insoluble cellulose such as microcrystalline cellulose, a-cellulose, cross-linked sodium carboxymethylcellulose, and their derivatives;
water-absorbing and water-insoluble hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, pectin and their derivatives;
water-absorbing and water-insoluble gum such as arabia gum, tragacanth gum, glucomannan and their derivatives;
and cross-linked vinyl polymers such as polyvinylpolypyridone, cross-linked polyacrylic acid and its salt, cross-linked polyvinyl alcohol, polyhydroxyethylmethacrylate and their derivatives. Among these, water-absorbing and water-insoluble cellulose is preferable, in particular, microcrystalline cellulose and its derivative are desirable.
It is also possible to add to this powder, in addition to the one or more types of peptide proteinaceous drugs, the absorption accelerant of the present invention, and above-mentioned substrate, according to requirement, a known lubricant, preservative, antiseptic, deodorant, etc.
As a lubricant, for example, mention may be made of talc, stearic acid and its salts, etc.; as a colorant, for example, mention may be made of copper chlorophyll, J3-carotene, red No. 2, blue No. 1, etc.; as a preservative, for example, mention may be made of stearic acid, ascorbic acid stearate, etc.; as an antiseptic, for example, mention may be made of benzylkonium chloride and other quaternary ammonium compounds, paraoxybenzoic acid esters, phenols, chlorobutanol, etc.; and as deodorant, mention may be made for example of menthol, citrus _2145302 fragrances, etc.
The peptide proteinaceous drug nasal powder of the present invention is usually administered in the nasal cavity by the following method. That is, a capsule filled with the powder to set for example in an exclusive spray apparatus possessing a needle, the needle is made to penetrate it to make fine holes at the top and bottom of the capsule, then air is fed by a rubber ball etc. to make the powder spray out.
EXAMPLES
The present invention will now be explained in more detail in accordance with the Reference Experiments and Examples, but of course the present invention is not limited to these Examples.
Reference Experiment 1 (1) A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml protein. To 0.5 ml portions of this homogenate were added 0.5 ml portions of an aqueous solution of salmon calcitonin (0.1 mg/ml). The results were incubated at 37 C, then the degradation fragments of the salmon calcitonin in the reaction liquid were separated by HPLC (L-6200 series (made by Hitachi, Ltd.) by 100% H20 from 0 to 5 minutes, 100% to 50% H20 and 0 to 50% acetonitrile from 5 to 55 minutes). The amino acid sequences of the separated fragments were determined by an amino-acid sequencer (made by Applied Biosystems). The first fragment of salmon calcitonin in human nasal mucosal homogenate are shown to Table 1.
Table 1: Degradation Fragments in Human Nasal Mucosal Membrane Homogenate Salmon calcitonin Cys-Ser-Asn-Leu-Ser-Thr-Cys-fragment 1 Val-Leu-Gly-Lys Salmon calcitonin Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-fragment 2 Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 As shown in Table 1, the C end side of Lys of the peptide proteinaceous drug is first cleaved in a human nasal mucosal homogenate. From this, it is guessed that the protease which first cleaves the peptide proteinaceous drug in the human nasal cavity is a trypsin-like enzyme.
A refined trypsin (made by Wako Pure Chemical Industry) was used, instead of the human nasal mucosal homogenate solution, in the same procedures followed as in (1) to separate the degradation fragments of salmon calcitonin in the reaction liquid by HPLC. In the same way as (1), the amino acid sequence was determined by an amino-acid sequencer. The results are shown in Table 2.
Table 2: Salmon Calcitonin Degradation Fraqments by Trypsin Fragment 1 Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys Fragment 1 Leu-Ser-Gln-Glu-Leu-His-Lys Fragment 1 Leu-Gln-Thr-Tyr-Pro-Arg Fragment 1 Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-As shown in Table 2, the degradation fragments of salmon calcitonin caused by refined trypsin are different from the degradation fragments of salmon calcitonin of Table 1. From this, it is guessed that the trypsin-like enzyme present in the human nasal cavity is not trypsin itself.
Reference Experiment 2 A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml of protein. Next, synthesis substrates corresponding to the various proteases shown in Table 1 were added to 0.5 ml portions of the homogenate solution to give 0.1 mM concentrations. The results were incubated at 37 C. The amounts of the substrates remaining after a predetermined time were measured by HPLC to find the amounts of substrates cleaved and find the activity of the various proteases.
The results are shown in Table 3.
Table 3: Activity of Protease in Human Nasal Mucosal Homogenate Synthesized substrate Corresponding Activity protease (nM/h/mg protein) Boc-Gln-Ala-Arg-MCA Trypsin 525 Boc-Val-Pro-Arg-MCA a-Thrombin 269 Boc-Phe-Ser-Arg-MCA Trypsin 250 Pro-Phe-Arg-MCA Kallikrein 85 Suc-Ala-Ala-Pro-Phe-MCA Chymotrypsin 24 Boc-Glu-Lys-Lys-MCA Plasmin 14 Suc-Ala-Ala-Ala-MCA Elastase 3 Bz-Arg-MCA Trypsin 1 In the synthesis substrates, Boc means a t-Butyloxycarbonyl group, Suc means a Succinyl group, Bz means a Benzyl group, and MCA means 4-Methyl-Coumaryl-7-Amide.
As shown in Table 3, a trypsin-like enzyme has a relatively high activity in human nasal mucosal homogenate, while plasmin has a considerably low activity. However, there were some substrates corresponding to trypsin (in Table 3, Bz-Arg-MCA) which do not cleave much at all. Also, it became clear that the enzyme present in the human nasal mucosal homogenate is not trypsin itself. That is, it is guessed that in the human nasal cavity, peptide proteinaceous drugs are mainly cleaved down by enzymes which are not trypsin, but have trypsin-like activity.
Reference Experiment 3 A homogenate solution was prepared from human nasal mucosa to give 1 mg/ml of protein. Next, 0.25 ml portions of aqueous solutions (72 mM) of the different peptide proteinaceous drugs were added to 0.5 ml portions of the homogenate solution, 0.01 ml portions of aqueous solutions (72M) of different enzyme inhibitors or absorption accelerants of the present invention were added, and the results were incubated at 37 C. The amounts of the peptide proteinaceous drug not yet cleaved after a predetermined time were measured by HPLC to find the amounts of decomposition. The inhibition rates were calculated by the following formula. The results are shown in Table 4.
Inhibition rate (A-B)/A x 100 A: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor or absorption accelerant of present invention is not added to homogenate B: Amount of peptide proteinaceous drug cleaved when enzyme inhibitor or absorption accelerant of present invention is added to homogenate E-ACA: E-Amino caproic acid SCT: Salmon calcitonin INS: Insulin GIF: Somatostatin ACTH: Adrenocorticotropic hormone PTH: Parathyroid hormone CGRP: Calcitonin gene related peptide GLU: Glucogon PDGF: Platelet-derived growth factor S.p: Substance P
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As shown in Table 4, it is clear that by including a trypsin inhibitor, the degradation of the peptide proteinaceous drug in the human nasal mucosal homogenate is obstructed. More surprisingly, it became clear that tranexamic acid, which is not a trypsin inhibitor, and other compounds of the present invention which are not trypsin inhibitors and are also not recognized as enzyme inhibitors, such as cyclohexane methylamine, cetraxate hydrochloride, rotraxate hydrochloride, benzylamine, p-aminomethyl benzoic acid, mafenide acetate, dopamine hydrochloride, etc. have a function of inhibiting the degradation of peptide proteinaceous drugs higher than the trypsin inhibitors of aprotinin and gabexate mesylate (Gabexate). This function is not observed in 6-amino caproic acid (E-ACA), so it is clear that it is not an inhibition function of plasmin. In other words, it is guessed that the enzymes which cleave peptide proteinaceous drugs in human nasal cavities are trypsin-like enzymes having the characteristic of being remarkably restrained in activity by compounds of the present invention like tranexamic acid, cyclohexane methylamine, rotraxate hydrochloride, cetraxate hydrochloride, benzylamine, p-aminomethyl benzoic acid, mafenide acetate, and dopamine hydrochloride.
Example 1 Salmon calcitonin in an amount of 40 g, tranexamic acid 40 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added calcitonin nasal powder.
The powder was weighed to give 100 IU (20 g) of calcitonin, was packed in No. 2 capsules, then was administered to the right nasal cavities of three normal human volunteers by a Publizer (registered trademark, Teijin). After administration, 5 ml of blood was taken from a vein in the forearm every certain period and the concentration of salmon calcitonin in the plasma was measured by the RIA method. The results are shown in Fig.
1 by the time curve of the concentration of salmon calcitonin in the plasma.
Control Example 1 The same procedure was followed as in Example 1, except that 40 g of tranexamic acid was not added, to prepare a tranexamic acid-free calcitonin nasal powder, the powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together in Fig. 1.
Control Example 2 The same procedure was followed as in Example 1, except that use was made of 0.4 mg of aprotinin instead of the 40 g of tranexamic acid in Example 1, to prepare an aprotinin-added calcitonin nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together in Fig. 1.
Example 2 Somatorein acetate (GHRH) in an amount of 2.0 mg, tranexam3.c acid 1.0 mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added GHRH nasal powder. The powder was weighed to give a 1.0 mg amount of GHRH, was packed in No. 2 capsules, and was administered to the right nasal cavities of three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of growth hormone (GH) in the plasma was measured. The results are shown together in Fig. 2 by the time curve of the concentration of GH in the plasma.
Control Example 3 The same procedure was followed as in Example 2, except that 1.0 mg of tranexamic acid was not added, to prepare a tranexamic acid-free GHRH nasal powder, the powder was weighed to give 1.0 mg of GHRH and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 2, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 2.
Control Example 4 The same procedure was followed as in Example 2, except that use was made of 2.0 mg of gabexate mesylate instead of 1.0 mg of tranexamic acid, to prepare a gabexate mesylate-added GHRH nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 2, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 2.
Example 3 Deslorelin (LHRH derivative) in an amount of 0.2 mg, tranexamic acid 0.2 mg, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a tranexamic acid-added LHRH derivative nasal powder. The powder was weighed to give 1.0 mg of the LHRH
derivative, was packed in No. 2 capsules, then was administered to the right nasal cavities of three normal human volunteers in the same way as in Example 1, then after a certain time the concentration of leuteinizing hormone (LH) in the plasma was measured. The results are shown in Fig. 3 by the time curve of the LH concentration in the plasma.
Control Example 5 The same procedure was followed as in Example 3, except that 0.2 mg of tranexamic acid was not added, to prepare a tranexamic acid-free LHRH derivative nasal powder, the powder was weighed to give 1.0 mg of LHRH
derivative and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 3, then after a certain time the concentration of GH in the plasma was measured. The results are shown together in Fig. 3.
Control Example 6 The same procedure was followed as in Example 3, except that use was made of 0.4 mg of aprotinin instead of 0.2 mg of tranexamic acid, to prepare an aprotinin-added LHRH derivative nasal powder, the powder was administered to three normal human volunteers in the same way as in Example 3, then after a certain time the concentration of LH in the plasma was measured. The results are shown in Fig. 3.
Example 4 Salmon calcitonin in an amount of 40 g, rotraxate hydrochloride 40 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar and mix to prepare a rotraxate hydrochloride-added calcitonin nasal powder. The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered in the right nasal cavity of three normal human volunteers by a Publizer (registered trademark, Teijin). After administration, 5 ml of blood was taken from a vein in the forearm every certain period and the concentration of salmon calcitonin in the plasma _ was measured by the RIA method. The results are shown in Fig. 4 by the time curve of the concentration of salmon calcitonin in the plasma together with the results of Comparative Examples 1 and 2.
Example 5 Salmon calcitonin in an amount of 40 g, mafenide acetate 60 g, microcrystalline cellulose 30 mg, and magnesium stearate 15 g were mixed in a mortar to prepare a mafenide acetate-added calcitonin nasal powder.
The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered in the right nasal cavity of three normal human volunteers by a Publizer (registered trademark).
After administration, 5 ml of blood was taken from a vein in the forearm every certain period of 5 minutes, 15 minutes, 30 minutes, and 60 minutes, and the concentration of salmon calcitonin in the plasma was measured by the RIA method. The results are shown in Fig.
5 by the time curve of the concentration of salmon calcitonin in the plasma.
Example 6 The same procedure was followed as in Example 5, except that use was made of 50 g of dopamine hydrochloride instead of 60 g of mafenide acetate, to prepare a dopamine hydrochloride-added calcitonin nasal powder. The powder was weighed to give 100 IU (20 g) of calcitonin and was packed in No. 2 capsules, then was administered to three normal human volunteers in the same way as in Example 5, then after a certain time the concentration of salmon calcitonin in the plasma was measured. The results are shown together with the results of the above-mentioned Comparative Examples 1 and 2 in Fig. 5.
INDUSTRIAL APPLICABILITY
According to the present invention, there is provided a peptide proteinaceous drug nasal powder composition which is improved in absorbency and a peptide _2145302 proteinaceous drug nasal powder composition which is improved in absorbency and safe to the body.
Claims (18)
1. A peptide proteinaceous drug nasal powder composition comprising (i) an absorption accelerant comprising a compound, or its salt, having in the compound molecule a group expressed by the formula (II):
wherein represents a cyclohexane ring or a benzene ring; n is an integer of 1 or 2; R1, R2 and R3 are, independently, a member selected from the group consisting of a hydrogen atom -COOR, -COR, -OR', and -SO2NH-, which may be substituted; provided that at least one of R1, R2 or R3 is a hydrogen atom; R represents a hydrogen atom, a C1-C6 lower alkyl group which may be substituted, or , R' represents a hydrogen atom, a C1-C6 lower alkyl group which may be substituted, a phenyl group which may be substituted, or a C7-C8 aralkyl group which may be substituted, and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
wherein represents a cyclohexane ring or a benzene ring; n is an integer of 1 or 2; R1, R2 and R3 are, independently, a member selected from the group consisting of a hydrogen atom -COOR, -COR, -OR', and -SO2NH-, which may be substituted; provided that at least one of R1, R2 or R3 is a hydrogen atom; R represents a hydrogen atom, a C1-C6 lower alkyl group which may be substituted, or , R' represents a hydrogen atom, a C1-C6 lower alkyl group which may be substituted, a phenyl group which may be substituted, or a C7-C8 aralkyl group which may be substituted, and (ii) a therapeutically effective amount of a peptide proteinaceous drug.
2. The nasal powder composition as set forth in claim 1, wherein the cyclic structure is cyclohexane ring and n= 1 in formula (II).
3. The nasal powder composition as set forth in claim 2, wherein the cyclohexane ring is substituted by a group selected from the group consisting of a hydrogen atom, -CO-C6H5-(CH2)2COOH, a carboxyl group, and -COO-C6H5-(CH2)2COOH.
4. The nasal powder composition as set forth in claim 2, wherein R1 and R3 in formula (II) are hydrogen atoms and R2 is -COO-C6H5-(CH2)2COOH.
5. The nasal powder composition as set forth in claim 2, wherein R1 and R3 in formula(II)are hydrogen atoms and R2 is -CO-C6H5-(CH2)2-COOH.
6. The nasal powder composition as set forth in claim 2, wherein R1 and R3 in formula (II) are hydrogen atoms and R3 is a carboxyl group.
7. The nasal powder composition as set forth in claim 1, wherein the cyclic structure in formula (II) is a benzene ring and n is 1 or 2.
8. The nasal powder composition as set forth in claim 7, wherein the benzene ring is substituted by a group selected from the group consisting of a hydrogen atom, carboxyl group, hydroxyl group and sulfamine group.
9. The nasal powder composition as set forth in claim 7, wherein R1 and R3 in formula (II) are hydrogen atoms and R2 is a carboxyl group and n is 1.
10. The nasal powder composition as set forth in claim 7, wherein R1 and R3 in formula (II) are hydrogen atoms, R2 is a sulfamine group, and n is 1.
11. The nasal powder composition as set forth in claim 7, wherein, in formula (II), R1 is a hydrogen atom, R2 and R3 are hydroxyl groups, and n is 2.
12. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of calcitonins, insulins, somatostatin (GIF) and its derivatives, parathyroid hormones (PTH), substance P, platelet derived growth factors (PDGF), galanin, gastrin, neurokinins, interleukins, neurotensin, endo serine, growth hormones (GH), growth hormone-releasing hormone (GHRH) and its derivatives, growth hormone releasing factor (GRF), luteinizing hormone-releasing hormone (LHRH) and its derivative, enkephalin and its derivatives, secretin, bradykinin and its derivative, adrenocortico-trophic hormone (ACTH) and its derivatives, glucagon, insulin growth factor (IGF), calcitonin gene related peptide (CGRP), interferons, vasopressin and its derivatives, atrial natrium peptide (ANP), erythropoietin, granulocyte colony stimuli factor (G-CSF), and macrophage colony stimuli factor (M-CSF).
13. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of calcitonins, insulins, somatostatin (GIF) and its derivatives, parathyroid hormones (PTH), substance P, platelet derived growth factors (PDGF), growth hormone-releasing hormone (GHRH) and its derivatives, luteinizing hormone-releasing hormone (LHRH) and its derivative, adrenocorticotrophic hormone (ACTH) and its derivatives, glucagon, and calcitonin gene related peptide (CGRP).
14. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group comprising salmon, eel, human, pig, and chicken natural calcitonins and their derivatives.
15. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of human, rat, and pig natural somatostatin and their derivatives.
16. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of bovine, human, and rat natural parathyroid hormone (PTH) and their derivatives.
17. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of bovine, human, rat, and pig natural luteinizing hormone-releasing hormone (LHRH) and their derivatives.
18. The nasal powder composition as set forth in any one of claims 1 to 11, wherein the peptide proteinaceous drug is at least one peptide proteinaceous drug selected from the group consisting of human, rat, and pig natural growth hormone-releasing hormone (GHRH) and their derivatives.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5/206922 | 1993-07-30 | ||
| JP20692293 | 1993-07-30 | ||
| JP5/235841 | 1993-08-30 | ||
| JP23584193 | 1993-08-30 | ||
| JP164494 | 1994-01-12 | ||
| JP6/1644 | 1994-01-12 | ||
| PCT/JP1994/001257 WO1995003818A1 (en) | 1993-07-30 | 1994-07-29 | Powder for nasal administration of peptidic or proteinaceous drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2145302A1 CA2145302A1 (en) | 1995-02-09 |
| CA2145302C true CA2145302C (en) | 2008-10-28 |
Family
ID=27275015
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002145302A Expired - Fee Related CA2145302C (en) | 1993-07-30 | 1994-07-29 | Peptide proteinaceous drug nasal powder composition |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5578324A (en) |
| EP (1) | EP0667163B1 (en) |
| JP (1) | JP2974412B2 (en) |
| KR (1) | KR100327563B1 (en) |
| AT (1) | ATE215377T1 (en) |
| CA (1) | CA2145302C (en) |
| DE (1) | DE69430295T2 (en) |
| ES (1) | ES2171459T3 (en) |
| WO (1) | WO1995003818A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| WO1995033474A1 (en) * | 1994-06-03 | 1995-12-14 | Tsumura & Co. | Medicinal composition |
| JP3263598B2 (en) * | 1995-11-01 | 2002-03-04 | 有限会社ドット | Bioactive peptide composition for nasal absorption |
| AU722319B2 (en) * | 1996-02-27 | 2000-07-27 | Teijin Limited | Powdery composition for nasal administration |
| DK1025859T3 (en) * | 1998-08-26 | 2006-10-16 | Teijin Ltd | Powdered pernasal preparations |
| CA2488497A1 (en) * | 2002-06-11 | 2003-12-18 | The Burnham Institute | Neuroprotective synergy of erythropoietin and insulin-like growth factor |
| US7812120B2 (en) * | 2003-03-21 | 2010-10-12 | Par Pharmaceutical, Inc. | Nasal calcitonin formulations containing chlorobutanol |
| JP2008019245A (en) * | 2006-06-15 | 2008-01-31 | Japan Science & Technology Agency | Intranasal agent for prevention and treatment of alzheimer's disease containing humanin derivative or fused peptide composed of humanin derivative and neurotropic peptide as active component |
| KR102259110B1 (en) * | 2016-11-28 | 2021-06-01 | 포라 가세이 고교 가부시키가이샤 | anti-wrinkle |
| JP7102658B2 (en) * | 2018-05-29 | 2022-07-20 | ポーラ化成工業株式会社 | Whitening composition |
| JP7102657B2 (en) * | 2018-05-29 | 2022-07-20 | ポーラ化成工業株式会社 | Wrinkle improving composition |
| SG11202011525WA (en) * | 2018-05-29 | 2020-12-30 | Pola Chem Ind Inc | Skin lightening agent |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258030A (en) * | 1979-03-07 | 1981-03-24 | Zeria-Shinyaku Kogyo Kabushiki Kaisha | Urokinase preparation for oral administration |
| DE3514508A1 (en) * | 1985-04-22 | 1986-10-30 | Kailash Kumar Prof. Dr. 2359 Lentföhrden Gauri | Use of dopamine and its esters for the treatment of glaucoma |
| JPH01308235A (en) * | 1988-06-03 | 1989-12-12 | Yamanouchi Pharmaceut Co Ltd | Human growth hormone for transnasal administration |
| GB9013448D0 (en) * | 1990-06-15 | 1990-08-08 | Sandoz Ltd | Pharmaceutical resorption-improved somatostatin compositions,their preparation and use |
| JPH04235923A (en) * | 1991-01-16 | 1992-08-25 | Kyowa Hakko Kogyo Co Ltd | Pharmaceutical preparation for nasal administration |
| JPH04300817A (en) * | 1991-03-27 | 1992-10-23 | Shiseido Co Ltd | Composition for oral cavity |
| JPH0558908A (en) * | 1991-09-05 | 1993-03-09 | Mitsubishi Kasei Corp | Medicinal composition for nasal drops of calcitonin |
| JP3090353B2 (en) * | 1991-09-17 | 2000-09-18 | 旭化成工業株式会社 | Emulsion for nasal administration containing parathyroid hormones |
| JP3047948B2 (en) * | 1992-12-07 | 2000-06-05 | 株式会社ツムラ | Composition for nasal administration of peptides |
-
1994
- 1994-07-29 AT AT94921840T patent/ATE215377T1/en not_active IP Right Cessation
- 1994-07-29 CA CA002145302A patent/CA2145302C/en not_active Expired - Fee Related
- 1994-07-29 JP JP7505744A patent/JP2974412B2/en not_active Expired - Fee Related
- 1994-07-29 ES ES94921840T patent/ES2171459T3/en not_active Expired - Lifetime
- 1994-07-29 KR KR1019950701216A patent/KR100327563B1/en not_active IP Right Cessation
- 1994-07-29 DE DE69430295T patent/DE69430295T2/en not_active Expired - Lifetime
- 1994-07-29 US US08/407,000 patent/US5578324A/en not_active Expired - Lifetime
- 1994-07-29 WO PCT/JP1994/001257 patent/WO1995003818A1/en active IP Right Grant
- 1994-07-29 EP EP94921840A patent/EP0667163B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| KR950703352A (en) | 1995-09-20 |
| KR100327563B1 (en) | 2002-08-24 |
| ATE215377T1 (en) | 2002-04-15 |
| DE69430295D1 (en) | 2002-05-08 |
| JP2974412B2 (en) | 1999-11-10 |
| EP0667163A4 (en) | 2000-04-19 |
| EP0667163B1 (en) | 2002-04-03 |
| EP0667163A1 (en) | 1995-08-16 |
| ES2171459T3 (en) | 2002-09-16 |
| WO1995003818A1 (en) | 1995-02-09 |
| DE69430295T2 (en) | 2002-10-31 |
| US5578324A (en) | 1996-11-26 |
| CA2145302A1 (en) | 1995-02-09 |
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