EP2344182A1 - HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUT - Google Patents
HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUTInfo
- Publication number
- EP2344182A1 EP2344182A1 EP09783807A EP09783807A EP2344182A1 EP 2344182 A1 EP2344182 A1 EP 2344182A1 EP 09783807 A EP09783807 A EP 09783807A EP 09783807 A EP09783807 A EP 09783807A EP 2344182 A1 EP2344182 A1 EP 2344182A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hpth
- seq
- derivatives
- ointment
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
Definitions
- the invention relates to the use of hPTH-1-37 for the manufacture of a medicament for the treatment of inflammatory-scaly diseases, the use of its derivatives for the manufacture of a medicament for the treatment of inflammatory-scaly diseases, a process for the preparation of hPTH-1-37 and a drug comprising hPTH-1-37 or its derivatives.
- Hemoparatide is the naturally occurring form of the parathyroid hormone parathyroid hormone (hPTH) processed from human blood (Hock et al., 1997).
- PTH is a vital, parathyroid-derived peptide that plays a key role in many metabolic functions. In particular, it regulates cell proliferation and differentiation of keratinocytes in the skin.
- Hemoparatide is the most important bioactive form of PTH in the human body, as evidenced by the efficacy and concentration of this peptide in blood plasma.
- the effects of hPTH on the Skin does not develop in the organism therefore not by the complete molecule, but by the processed form hPTH-1-37.
- US-B-6066618 discloses a method for inhibiting the proliferation of mammalian skin cells, wherein hPTH 1-34 is used as the antiproliferative peptide. Furthermore, in DE-A-19508672 cyclic parathyroid hormone fragments of z. B. hPTH (I-34) discloses which u. a. can be used to treat psoriasis. Both disclosures have foreign derivatives of human parathyroid hormone in the content, which are therefore expected to be more adverse effects and a poorer bioavailability.
- WO-A-2004/024758 discloses parathyroid hormone peptides from fish. These are u. a. for the treatment of psoriasis.
- US-A-2007/0117157 describes the treatment of psoriasis with parathyroid hormone peptides from fish.
- the PTH derivatives described therein have an amino acid homology of only 53% to human PTH and have a markedly altered biological activity.
- WO 02/28420 relates to methods of regulating cell differentiation and proliferation, e.g. for the treatment of psoriasis by administration of nucleic acid molecules encoding PTH.
- WO-A-89/03873 relates to the regulation of cell proliferation by using peptides such as PTH (1-34). However, this application does not relate to PTH peptides 1-37.
- WO 2005-A-007184 relates to cyclic analogs of hPTH.
- WO-A-2008/150929 relates to topically administrable composition comprising hPTH 1-37 for the treatment of psoriasis in certain galenic preparations.
- the chemical synthesis of Hemoparatide has been carried out by several producers, providing the product for preclinical and clinical investigations and studies.
- the synthesis of hPTH is not trivial, so even products with high levels of impurities in incompletely synthesized peptides have been marketed.
- An object of the present invention is to provide a high purity form of hemoparatide for use as a therapeutic.
- galenic forms In addition to the purity requirements of hemoparatides, galenic forms must be found that optimize the use of the high-purity peptide, are adapted to the status and purpose of the treatment, and allow Hemoparatide to be used locally in inflammatory scaly (erythemato-squamous) skin conditions . Such formulations for Hemoparatide, even in highly pure form, are not yet available. Therefore, for today's regulations on the one hand, a sufficiently pure active substance must be available, which on the other hand can be provided in appropriate galenic forms, moreover can be produced commercially, and thus can be regarded as a highly pure form with the highest demands. A further object can thus be seen to provide the high-purity hPTH to be provided in a suitable pharmaceutical dosage form.
- An object of the present invention is the use of hPTH-1-37 with the amino acid sequence SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVAL (SEQ ID NO: 1) for the manufacture of a medicament for the treatment of inflammatory-scaly (erythemato-squamous) diseases, in particular psoriasis.
- hPTH-1-37 has a molecular weight of 4401.13 Da.
- Another object of the present invention are derivatives of hPTH-1-37, namely their natural and pharmacologically acceptable derivatives, in particular amidated, acylated, phosphorylated and glycosylated derivatives for the manufacture of a medicament for the treatment of inflammatory scaly (erythemato-squamous) diseases, in particular psoriasis ,
- Another aspect of the invention is a process for the preparation of hPTH-1-37 or its derivatives, characterized in that they are synthesized by chemical synthesis from the partial sequences SVSEIQLMHNL (SEQ ID No. 2) and GKHLNSMERVEWLRKKLQDVHNFVAL (SEQ ID No. 3) or SVSEIQLMHNL (SEQ ID No. 2), GKHLNSMERVEW (SEQ ID No. 4) and LRKKLQDVH N FVAL (SEQ ID No. 5) are prepared and purified by chromatography.
- the hemoparatides (hPTH-1-37) or its derivatives are used for the preparation of a medicament in various pharmaceutical application forms, in particular as a lyophilisate.
- a hydrophilic ointment is used in particular according to the German Pharmacopoeia as a galenic basis of application. It has surprisingly been found that the active substance is very stable except for methionine-oxidized metabolites in this formulation. These oxidized metabolites also occur as natural PTH forms in the blood plasma, but can be avoided by working in a nitrogen atmosphere and are free from side effects as naturally occurring endogenous derivatives.
- a further aspect of the invention is a pharmaceutical composition containing from 300 micrograms to 30 milligrams of hPTH-1-37 per gram of preparation (SEQ ID No. 1) and / or from 300 micrograms to 30 milligrams of its derivatives.
- the formulation in one embodiment contains typical ointment bases into which the peptide hPTH-1-37 is incorporated.
- a typical ointment contains:
- Emulsifying cetylstearyl alcohol type A 15-25 g, in particular 21 g
- Anhydrous citric acid 0.01 - 1.5 g, especially 0.07 g
- Benzalkonium chloride 50-200 mg, especially 100 mg
- the amount of hPTH 1-37 may be 0.01 to 1.0% by weight based on the ointment base.
- Figure 1 discloses an HPLC chromatogram of the high purity hemoparatide
- FIG. 2 shows a MALDI (matrix assisted laser desorption / ionization) MS spectrum of hPTH (l-37) end product.
- Figure 3 discloses a chromatogram of capillary zone electrophoresis (CZE) of hPTH (l-37) end product.
- Figures 4A and 4B disclose HPLC chromatograms of hPTH- (1-37).
- Figure 4A shows a chromatogram of freshly prepared hPTH- (1-37).
- Figure 4B is a chromatogram of nine months of stored hPTH- (1-37).
- Figure 5 discloses the comparison between the HPLC chromatograms of freshly prepared hPTH-1-37
- the peptides of the invention are prepared by chemical synthesis in solution or on the solid support. This can be different
- the peptides according to the invention can be obtained from the protected peptide fragment by convergent synthesis.
- the temporary Fmoc protecting groups were cleaved with 20% piperidine in N-methyl-2-pyrrolidinone within 2-10 minutes. After removal of the Fmoc protecting group, the peptidyl resin was washed thoroughly and repeatedly with NMP followed by dichloromethane and dried. The dry resin was then suspended to cleave the peptide in a freshly prepared mixture of trifluoroacetic acid, ethanedithiol and water (94: 3: 3, vol, 20 ml per 1 g peptidyl resin) and shaken for three hours. The mixture was filtered, the residue was washed with further elimination mixture and the combined filtrates are added slowly with cooling to 10 times the volume of cold tert-butyl methyl ether. The precipitated deprotected peptidic material was stored overnight at + 4 ° C and then isolated by filtration or centrifugation and dried in vacuo.
- the crude peptide was dissolved in 10% acetic acid and purified by chromatography (Waters Prep-Pak C18, 47 x 300 mm, eluent A: 0.7% trifluoroacetic acid (TFA) in water, eluant B: 0.7% TFA in acetonitrile / water 4 : 1 (vol), gradient: 35-55% Eluent B in 40 minutes, detection: UV at 215 nm, flow rate: 40 ml / min). Fractions containing the product in sufficient purity (determined by analytical HPLC) were combined and freeze-dried.
- TFA trifluoroacetic acid
- the dry product was taken up in 10% acetic acid and chromatographed in the presence of acetic acid / acetate (Waters Prep-Pak C18, 47 x 300 mm, equilibrated with 0.1 M ammonium acetate solution, eluent A: 10% acetic acid in Water: eluent B: 2% acetic acid in acetonitrile / water 4: 1 (vol), gradient: 10-60% eluent B in 40 minutes, detection: UV at 215 nm, flow rate: 40 ml / min). Fractions of sufficient purity were combined and freeze-dried.
- Tab. 1 The essential specifications that are used for the shape of the peptide as a high-purity product.
- the galenic application are preferably creams on an oil-in-water basis, in the aqueous phase, the water-soluble hemoparatide is incorporated.
- Hemoparatide was incorporated into this base in concentrations of 0.03 wt%, 0.1 wt% and 0.3 wt%.
- the active substance is very stable except for methionine-oxidized metabolites in this formulation.
- These oxidized metabolites also occur as natural PTH forms in the blood plasma, but can be avoided by working in a nitrogen atmosphere and are free from side effects as naturally occurring endogenous derivatives.
- To use the cream formulation it is applied as usual in galenic units preferably twice a day thinly on the skin.
- the hPTH-1-37 cream was applied twice a day thinly on the lateral calf area to the right, dorsal to the arrows:
- the treated area has an area of approx. 4 x 10 cm.
- the ointment per application contains a total of> 20 ⁇ g hPTH-1-37, ie 40 ⁇ g per day.
- Left picture shows the right lower leg before treatment, right picture after 14 days of treatment.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09783807A EP2344182A1 (de) | 2008-10-07 | 2009-10-07 | HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUT |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08166024 | 2008-10-07 | ||
EP09783807A EP2344182A1 (de) | 2008-10-07 | 2009-10-07 | HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUT |
PCT/EP2009/063017 WO2010040769A1 (de) | 2008-10-07 | 2009-10-07 | HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUT |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2344182A1 true EP2344182A1 (de) | 2011-07-20 |
Family
ID=40802091
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09783807A Withdrawn EP2344182A1 (de) | 2008-10-07 | 2009-10-07 | HERSTELLUNG UND VERWENDUNG VON HOCHREINEM HEMOPARATIDE (hPTH-1-37) FÜR DIE BEHANDLUNG VON ENTZÜNDLICH-SCHUPPENDEN ERKRANKUNGEN DER HAUT |
Country Status (3)
Country | Link |
---|---|
US (1) | US20110263509A1 (de) |
EP (1) | EP2344182A1 (de) |
WO (1) | WO2010040769A1 (de) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5512278A (en) * | 1994-01-11 | 1996-04-30 | Phylomed Corporation | Ointment base useful for pharmaceutical preparations |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0415924B1 (de) * | 1987-10-20 | 1996-05-29 | HOLICK, Michael F | Regulierung der zellenproliferation und differenzierung mittels peptiden |
DE19957918A1 (de) * | 1999-11-25 | 2001-06-13 | Ulrich Doht | Desinfektionsreiniger zur Reinigung und Pflege sowie Verfahren zu seiner Herstellung |
JP2004500404A (ja) * | 2000-03-27 | 2004-01-08 | カール − ツァイス − シュティフツング | 生物活性ガラスを含む新規化粧品、ボディケア、洗浄剤および栄養サプリメント組成物および製造方法およびその使用 |
US7906480B2 (en) * | 2002-05-23 | 2011-03-15 | Michael Holick | Use of a parathyroid hormone peptide analogs for the treatment of vaginal atrophy |
US20080299228A1 (en) * | 2007-05-29 | 2008-12-04 | Alan Gerald Harris | Topical compositions comprising a macromolecule and methods of using same |
-
2009
- 2009-10-07 EP EP09783807A patent/EP2344182A1/de not_active Withdrawn
- 2009-10-07 WO PCT/EP2009/063017 patent/WO2010040769A1/de active Application Filing
- 2009-10-07 US US13/123,046 patent/US20110263509A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5512278A (en) * | 1994-01-11 | 1996-04-30 | Phylomed Corporation | Ointment base useful for pharmaceutical preparations |
Non-Patent Citations (2)
Title |
---|
PKH GMBH: "Anionische hydrophile Creme SR (NRF S.27.)", 24 July 2012 (2012-07-24), Retrieved from the Internet <URL:http://www.apomix.de/downloads/produkte/pruefvorschrift-unguentum-emulsificans-aquosum-sr-k-256-190712.pdf> [retrieved on 20151125] * |
See also references of WO2010040769A1 * |
Also Published As
Publication number | Publication date |
---|---|
US20110263509A1 (en) | 2011-10-27 |
WO2010040769A1 (de) | 2010-04-15 |
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