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Número de publicaciónWO1997003692 A1
Tipo de publicaciónSolicitud
Número de solicitudPCT/DK1996/000293
Fecha de publicación6 Feb 1997
Fecha de presentación28 Jun 1996
Fecha de prioridad14 Jul 1995
También publicado comoCA2226523A1, CN1190897A, EP0839049A1
Número de publicaciónPCT/1996/293, PCT/DK/1996/000293, PCT/DK/1996/00293, PCT/DK/96/000293, PCT/DK/96/00293, PCT/DK1996/000293, PCT/DK1996/00293, PCT/DK1996000293, PCT/DK199600293, PCT/DK96/000293, PCT/DK96/00293, PCT/DK96000293, PCT/DK9600293, WO 1997/003692 A1, WO 1997003692 A1, WO 1997003692A1, WO 9703692 A1, WO 9703692A1, WO-A1-1997003692, WO-A1-9703692, WO1997/003692A1, WO1997003692 A1, WO1997003692A1, WO9703692 A1, WO9703692A1
InventoresThorkild Christensen, Per Balschmidt, Hans Holmegaard Soerensen, Ole Hvilsted Olsen, Lars Thim
SolicitanteNovo Nordisk A/S
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos:  Patentscope, Espacenet
A stabilized pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions
WO 1997003692 A1
Resumen
A pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions shows a very high stability against deamidation, oxidation and cleavage of peptide bonds. The stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved formulation at ambient temperature.
Reclamaciones  (El texto procesado por OCR puede contener errores)
1. A pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions.
2. A pharmaceutical formulation as claimed in claim 1 fur¬ ther comprising a carrier in the form of a buffered aqueous solution of growth hormone pre-treated with zinc and optionally lysine or calcium ions.
3. A pharmaceutical formulation as claimed in claim 1 or 2 wherein the pH is adjusted to a value in the interval from about 2 to about 9.
4. A pharmaceutical formulation as claimed in any of the preceding claims wherein the concentration of zinc is up to about 2 mM.
5. A pharmaceutical formulation as claimed in any of the preceding claims further comprising salts and/or saccharides and/or sugar alcohols.
6. A pharmaceutical formulation as claimed in any of claims 1-5 wherein the growth hormone is hGH.
7. A method of preparing a pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions wherein the growth hormone is dissolved in a solution comprising zinc and optionally lysine or calcium ions by dissolving zinc chloride in deionized water optionally containing lysine or calcium ions, letting the solution stand for a while, adding the growth hormone, optionally adding a preservative, and optionally adjusting the pH to from about 2 to about 9.
8. A method as claimed in claim 7, wherein is added optionally salts and/or sugar alcohols and an excipient, whereafter the solution is filled into a container and lyophilized.
9. Use of zinc and optionally lysine or calcium ions for pre-treatment of growth hormone for the formulation of a stabilized formulation of growth hormone.
10. A method for treating a disorder affectable by growth hormone deficiency, comprising administering the formulation of claim 1.
Descripción  (El texto procesado por OCR puede contener errores)

TITLE

A STABILIZED PHARMACEUΗCAL FORMULATION COMPRISING A GROWTH HORMONE PRE-TREATEDWITHZINC ANDOPTIONALLYLYSINEORCALCIUMIONS

FIELD OF THE INVENTION

The present invention relates to a stabilized pharmaceutical formulation comprising growth hormone, to a method of making such formulation, to the use of zinc for stabilizing a for- mulation of growth hormone, and to a method for treating a disorder affectable by growth hormone.

BACKGROUND OF THE INVENTION

The growth hormones from man and from the common domestic animals are proteins of approximately 191 amino acids, syn¬ thesized and secreted from the anterior lope of the pitui¬ tary gland. Human growth hormone consists of 191 amino acids.

Growth hormone is a key hormone involved in the regulation of not only somatic growth, but also in the regulation of metabolism of proteins, carbohydrates and lipids. The major effect of growth hormone is to promote growth.

The organ systems affected by growth hormone include the skeleton, connective tissue, muscles, and viscera such as liver, intestine, and kidneys.

Until the development of the recombinant technology and the cloning of the growth hormone gene now giving rise to production of e.g. human growth hormone (hGH) and Met-hGH in industrial scale, human growth hormone could only be obtained by extraction from the pituitary glands of human cadavers. The very limited supplies of growth hormone restricted the use thereof to longitudinal growth promotion in childhood and puberty for treatment of dwarfism, even though it has been proposed for inter alia treatment of short stature (due to growth hormone deficiency, normal short stature and Turner syndrome) , growth hormone deficiency in adults, infertility, treatment of burns, wound healing, dystrophy, bone knitting, osteoporosis, diffuse ga¬ stric bleeding, and pseudoarthrosis.

Furthermore, growth hormone has been proposed for increasing the rate of growth of domestic animals or for decreasing the proportion of fat in animals to be slaughtered for human consumption.

Pharmaceutical formulations of growth hormone tend to be un¬ stable. Degradation products such as deamidated or sulfoxy- dated products and dimer or polymer forms are generated - especially in solutions of growth hormone.

The predominant degradation reactions of hGH are 1) deamida¬ tion by direct hydrolysis or via a cyclic succinimide intermediate to form various amounts of L-asp-hGH, L-iso- asp-hGH, D-asp-hGH, and D-iso-asp-hGH (ref 1-3), and 2) oxidation of the methionine residues in positions 14 and 125 (ref 4-9) . The major degradation product of hGH in lyophilized state as well as in solution is deamidated hGH.

Deamidation especially takes place at the Asn in position 149 and to a minor extent in position 152.

hGH is also rather easily oxidized in positions 14 and 125.

The oxidation of hGH in solution forming sulfoxides is nor¬ mally due to the oxygen dissolved in the formulation. The solubility of oxygen in distilled water is about 200 μM (9) . As the concentration of hGH in a formulation comprising 4 IU/ml is 1.3 mg/ml corresponding to 60nM hGH, oxygen will, at normal storing conditions, be present in an excess of about 3000 times the stoichiometric amount for oxidation of hGH. It is not feasible to try to solve the problem by degassing of buffers before tapping and packing the formulations.

At present, it is not believed that these deamidated forms and oxidized forms of hGH should have toxic or altered biological activity or receptor binding properties, but there is indication to the effect that the conformation stability of the sulfoxides is reduced as compared to native hGH.

For the development of a stable, dissolved formulation com¬ prising hGH it is of importance to know the rate of deamida¬ tion and formation of sulfoxides as well as means to control the reactions.

The kinetics of degradation depend on temperature, pH and various additives or adjuvants in the hGH formulation.

Due to the instability, growth hormone is, at present, lyophilized and stored in the lyophilized form at 4°C until it is reconstituted for use in order to minimize the degradation.

The lyophilized pharmaceutical formulations comprising hGH are, at present, reconstituted by the patient and then stored as a solution during the use for a period of up to 14 days at 4°C, during which some degradation will take place.

Furthermore, the process of reconstitution of the lyophilized growth hormone tends to provide difficulties for the patient.

Thus, it is at present preferred to reconstitute the growth hormone as late as possible before use and to store and ship the formulation in a lyophilized state. The chain from the manufacturer to the pharmacy is apt for handling the formulations at a controlled low temperature of e.g. 4°C which allows for a long shelf life of up to two years.

However, the extended use of pen systems for self-medication and the expanded field of use calls for a formulation which is stable for a sufficient long time with the end user under conditions where "sufficient" cooling is not always avai¬ lable.

Preferably, a formulation should be stable with the end user in a lyophilized state for about one month and additionally for one month in a reconstituted state in a pen device for the intended period of use of a cartridge.

Thus, there is a need for more stable formulations of growth hormone being stable in a lyophilized state at a relative high temperature for a period and additionally for a period of use at a relatively high temperature in solution. Such stabilization is of very great importance when moving the administration of the growth hormone from clinics to the ho¬ mes of the individuals to be treated where optimal storage may not be available as indicated above.

Furthermore, the shift in pattern of administration of growth hormone to the use of pen devices calls for a stable dissolved formulation comprising growth hormone in order to facilitate the handling to be- performed by the patient. A stable dissolved formulation comprising growth hormone may be produced ready to use in the form of cartridges fitting into the pen device used by the patient who may then avoid the reconstitution of the formulation and, hence, will not have to be in the possession of a lyophilized formulation, a suitable vehicle for reconstitution as well as the necessary skill and sterile equipment for sterile reconstitution of the formulation. For safety reasons it will also be desirable to avoid the reconstitution of a lyophilized formulation just before the use of the formulation.

Furthermore, it would also be an advantage to avoid the lyo¬ philization step in the production of growth hormone formulations. Lyophilization is a time consuming and costly process and is also often a "bottleneck" in the production due to the limited capacity of the freeze drier.

Thus, there is a need to reduce the rate of the degradation processes in order to allow for dissolved hGH formulations being stable during shelf life and during the period of use of up to one month.

Prior attempts to stabilize hGH has not fully succeeded in preventing the formation of dimer. The problems associated with dimer formation is e.g noted in Becker, G. ., Biotech- nology and Applied Biochemistry 9, 478 (1987) .

International Patent Publication No. WO 89/09614 and Austra¬ lian patent application No. 30771/89 disclose a stable phar¬ maceutical formulation containing human growth hormone, gly- cine, and mannitol. Such a formulation shows improved stabi¬ lity during normal processing and storage in a lyophilized state as well as in the period of use after the reconstitu¬ tion.

Published European patent application No. 303 746 discloses that animal growth hormone may be stabilized with various stabilizers to give decreased formation of insolubles and preservation of the soluble activity in aqueous environments, such stabilizers including certain polyols, amino acids, polymers of amino acids having a charged side group at physiological pH, and choline salts. Polyols are selected from the group consisting of non-reducing sugars. sugar alcohols, sugar acids, pentaerythritol, lactose, water-soluble dextrans and Ficoll; amino acids are selected from the group consisting of glycine, sarcosine, lysine or salts thereof, serine, arginine or salts thereof, betaine, N,N, -dimethyl-glycine, aspartic acid or salts thereof, glutamic acid or salts thereof; a polymer of an amino acid having a charged side group at physiological pH may be selected from polylysine, polyaspartic acid, polyglutamic acid, polyarginine, polyhistidine, polyornithine and salts thereof; and choline derivatives are selected from the group consisting of choline chloride, choline dihydrogen citrate, choline bitartrate, choline bicarbonate, tricholine citrate, choline ascorbate, choline borate, choline gluconate, choline phosphate, di (choline) sulphate and dicholine mucate.

US patent specification No. 4,917,685 discloses a delivery device designed to be implanted comprising growth hormone stabilized using the same stabilizers as mentioned in EP 303746.

Published European patent application No. 374,120 discloses a stabilized formulation comprising hGH and a polyol having three hydroxy groups. Glycerol and tris (hydroxymethyl) amino¬ methane are mentioned. Furthermore, the presence of histidine hydrochloride as a buffer together with the polyol is disclosed.

International Patent Publication No. WO 92/00998 discloses that crystals may be formed crystallizing growth hormone with zinc.

International Patent Publication No. WO 93/12811 discloses stabilized formulations of growth hormone in the form of a lyophilized powder or an aqueous solution comprising asparagine. International Patent Publication No. WO 93/12812 discloses stabilized formulations of growth hormone in the form of a lyophilized powder or an aqueous solution comprising histi¬ dine. In such formulations the deamidation is reduced by 25- 30% as compared to a corresponding formulation of growth hormone comprising phosphate buffer. Furthermore, it "is disclosed that crystals may be formed crystallizing growth hormone with zinc in the presence of histidine.

International Patent Publication No. WO 93/19776 discloses protein formulations comprising growth hormone comprising citrate as buffer substance being more stable than formula¬ tions comprising phosphate buffer. The formulations may also comprise amino acids such as glycine and alanine and/or man- nitol or other sugar alcohols and/or glycerol and/or other carbohydrates and optionally a preservative such as benzyl alcohol.

International Patent Publication No. WO 94/03198 discloses a stable aqueous formulation containing human growth hormone, a buffer, a non-ionic surfactant, and, optionally, a neutral salt, mannitol, or, a preservative.

Published European patent application No. 177,478 discloses a prolonged release composition comprising zinc and somatotropin in a continuous phase with a biocompatible oil.

Published European patent application No. 216,485 discloses a sustained-release composition comprising zinc and somatotropin in a vehicle comprising a vegetable oil and an adjuvant, especially beeswax, aluminum monostearate, camauba wax or paraffin.

Published European patent application No. 277,043 discloses recovering somatotropin from an aqueous solution by adding a salt of a transition metal and precipitation of an insoluble complex. International Patent Publication No. WO 93/13792 discloses a delayed release implantable device comprising a somatotropin and zinc and optionally a basic side group containing amino acid solubilizing Zn-somatotropin, arginine, alanine, histidine and glutamic acid being mentioned as examples of amino acids.

International Patent Publication No. WO 92/17200 discloses stable growth hormone metal ion formulations in the form of dimers showing stability to denaturation. The formulations may comprise glycine and optionally additionally alanine, glutamine, asparagine, arginine or lysine, such amino acids being particularly advantageous when lyophilizing the formulation to create a sufficient mass to form a stable, dry caked formulation.

BRIEF DESCRIPTION OF THE INVENTION

It has now surprisingly been found that a formulation of hu¬ man growth hormone with zinc and optionally lysine or cal¬ cium ions before preparation of the final formulation shows a very high stability against deamidation in aqueous solution and is furthermore readily dissolvable in aqueous solvents when lyophilized. The stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved formula¬ tion.

The pharmaceutical formulations of the invention may be formulated for administration in any suitable way, e.g. by parenteral or oral administration or administration to a mucosal membrane, e.g. nasal administration. The pharmaceutical formulation may be presented in the form of a dose comprised in a vial or cartridge or any other suitable container such as a prefilled syringe or a pen device. Thus, the formulation of the invention may be in the form of a lyophilized powder to be reconstituted later using conven¬ tional vehicles such as distilled water or water for injec- tion or in the form of a solution comprising growth hormone. Such vehicles may comprise conventional preservatives such as phenol, m-cresol and benzyl alcohol.

A preferred embodiment of the invention is in the form of a pharmaceutical formulation of human growth hormone pre¬ treated with zinc and optionally lysine or calcium ions and further comprising a carrier in the form of a buffered ague¬ ous solution of growth hormone. Such formulation is in a ready-to-use form and may be stored and shipped as an aque- ous solution without any considerable degradation.

A buffer to be used in a solution of pre-treated growth hor¬ mone may e.g. be histidine, citrate, tartrate or phosphate buffer. Preferably, the buffer is histidine buffer.

The pre-treatment solution is preferably adjusted to a value in the interval from about 2 to about 9, more preferred to pH from 6 to 8, especially to about 7-7.3.

For stability reasons the pH in the final formulation of pre-treated growth hormone is preferably adjusted to a value of about 2 to about 9, more preferred to a value of about 6 to about 8, especially to a value of about 6.0 to about 6.8.

In order to obtain the stabilizing effect of zinc and optionally lysine or calcium ions zinc is preferably added in an amount of up to 2mM, preferably from about 1 to about 4 moles Zn per mol of growth hormone, preferably about 1 to 2 moles Zn per mole growth hormone, most preferred about 1 mol Zn per mol growth hormone. Zinc is preferably added in the form of a physiologically acceptable soluble salt such as the chloride.

Calcium ions when present are preferably added in the form of a physiologically acceptable soluble salt such as the chloride.

The pharmaceutical formulation of the invention may further¬ more comprise salts or sugar alcohols for adjusting the tonicity and optionally an excipient in order to facilitate the processing thereof, e.g. lyophilization and the rapid and complete dissolution of a lyophilized formulation when reconstituting the formulation before use.

An excipient may be selected from disaccharides such as lac¬ tose, trehalose, and sucrose, sugar alcohols such as sorbitol or mannitol, polysaccharides such as the polymers commercialized as Dextran® products such as Dextran® 40,

Dextran® 70 or Dextran® 75, and Ficoll® and polyvalent alcohols such as polyethylene glycol or polyvinyl alcohol or a combination of two or more of these.

In a further aspect the invention relates to a method of preparing a pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions wherein the growth hormone is dissolved in a solution comprising zinc and optionally lysine or calcium ions by dissolving zinc chloride in deionized water optio¬ nally containing lysine or calcium ions, letting the solution stand for a while, adding the growth hormone and optionally adjusting the pH to from about 2 to about 9.

The pH may be adjusted by adding an acid which has no adverse effect on the growth hormone, preferably a physiologically acceptable acid e.g. a mineral acid such as hydrochloric acid, sulphuric acid or nitric acid or an organic acid such as acetic acid. In an embodiment of the method of the invention, is added optionally salts and an excipient, whereafter the solution is filled into a container and lyophilized.

Still another aspect of the invention relates to the use of zinc and optionally lysine or calcium ions for pre-treatment of growth hormone for the formulation of a stabilized formu¬ lation of growth hormone.

In yet another aspect the invention relates to a method for treating a disorder affectable by growth hormone comprising administering a formulation which comprises a growth hormone pre-treated with zinc and optionally lysine or calcium ions.

In the present context "growth hormone" may be growth hormone from any origin such as avian, bovine, equine, human, ovine, porcine, salmon, trout or tuna growth hormone, preferably bovine, human or porcine growth hormone, human growth hormone being most preferred. The growth hormone used in accordance with the invention may be native growth hormone isolated from a natural source, e.g. by extracting pituitary glands in a conventional manner, or a growth hormone produced by recombinant techniques, e.g as described in E.B. Jensen and S. Carlsen in Biotech and Bioeng. 3_6, 1- 11 (1990) . The "growth hormone" may also be a truncated form of growth hormone wherein one or more amino acid residues has (have) been deleted; an analogue thereof wherein one or more amino acid residues in the native molecule has (have) been substituted by another amino acid residue, preferably a natural amino acid residue, as long as the substitution does not have any adverse effect such as antigenicity or reduced action; or a derivative thereof, e.g having an N- or C- terminal extension such as Met-hGH. The preferred growth hormone is hGH. The term "dose" of growth hormone refers to that amount that provides therapeutic effect in an administration regimen. The formulations hereof are prepared containing amounts of hGH at least about 0.1 mg/ml, preferably upwards of about 10 mg/ml, preferably from about 1 mg/ml to about 40 mg/ml, more preferably from about 1 mg/ml to about 25 mg/ml, e.g. from 1 mg/ml to about 5 mg/ml, calculated on the ready-to-use formulation. For use of these compositions in administration to human beings suffering from hypopituitary dwarfism, for example, these formulations contain from about 0.1 mg/ml to about 10 mg/ml, corresponding to the currently contemplated dosage regimen for the intended treatment. The concentration range is not critical to the invention and may be varied by the physician supervising the administration.

Lysine to be used in accordance with the present invention is preferably the naturally occurring alpha amino acid. The lysine may be 1 or d lysine or a mixture thereof.

In the present context "high stability" is obtained when the formulation is more stable than the conventional formulation comprising phosphate buffer and preferably as stable as a corresponding formulation comprising histidine as stabilizer in which the deamidation of hGH is reduced by approximately 20% as compared with phosphate buffer as disclosed in WO 93/12812.

The solvent used in the method of the invention may be water, alcohols such as ethyl, n-propyl or isopropyl, butyl alcohol or mixtures thereof. The solvent may comprise a preservative such as phenol, m-cresol or benzyl alcohol. The term "pre-treated" is used in the present context in connection with growth hormone formulations to designate a growth hormone which is treated with zinc and optionally lysine or calcium ions before the addition of or to the further components for preparation of a growth hormone for¬ mulation.

DETAILED DESCRIPTION OF THE INVENTION

The invention is explained more in detail in the below Exam¬ ples which illustrate the invention. They are not to be con¬ sidered as limiting the scope of the invention being defined by the appended claims.

EXPERIMENTAL PART

EXAMPLE

Reduction of the deamidation.

The rate of deamidation after different pre-treatments was examined at 37°C for hGH formulations containing 4 mg/ml hGH, 0.18 mM ZnCl2, 3 mM histidine, 1.5% benzyl alcohol, pH 6.8 as compared to histidine and phosphate buffer at pH 6.8.

The hGH formulations were prepared by dissolving 24 mg hGH in 2.5 ml of a) 2 mM CaC122 + 0.36 mM ZnCl2, pH 7-7.3, b) 2 M lysine + 0.36 mM ZnCl2, pH 7-7.3 or c) 0.36 mM ZnCl2, pH 7-7.3.

After storage 1 h at 4°C (to allow Zn++ to complex with hGH) the preparations a)-c) were reformulated using a PD10 desalting column (Pharmacia) into 3 ml 6 mM histidine, 0.36 mM ZnCl2, 8 mg/ml hGH. Thereafter 3 ml 3% benzyl alcohol were added resulting in a final formulation of 4 mg/ml hGH, 3 mM histidine, 0.18 mM ZnCl2, 1.5% benzyl alcohol, (pH adjusted to 6.8 adding HCl/NaOH) .

As reference formulations were used a) 4mg/ml hGH, 3 mM histidine, 0.18 mM ZnCl2 1.5% benzyl alcohol, pH 6.8; b) 4mg/ml hGH, 3 mM histidine, 1.5% benzyl alcohol, pH 6.8; and c) 4 mg/ml hGH, 3 mM Na2HP04, 1.5% benzyl alcohol, pH 6.8. The reference formulations were not pre-treated with Zn++.

The hGH formulations stated in the below table were stored at 37°C for 7 days, and analyzed for the content of deamidated hGH by IE-HPLC. The results appear from the below table

Formulation pHstart /pHend Content of Content of deamidated deamidated hGH forms as

(%)# compared with histidi-ne (%)

3 mM histidine, 0.18 mM 6.78/6.84 10.0 84

ZnCl2, 1.5% benzyl alcohol, pH 6.8.

Pre-treated in accor¬ dance with procedure a)

3 mM histidine, 0.18 mM 6.75/6.83 11.3 88

ZnCl2, 1.5% benzyl alcohol, pH 6.8.

Pre-treated in accor¬ dance with procedure b)

3 mM histidine, 0.18 6.79/6.87 11.5 89 mM ZnCl2, 1.5% benzyl alcohol, pH

6.8.

Pre-treated in accordance with procedure c)

3 mM histidine, 0.18 mM 6.84/6.92 12.8 99

ZnCl2, 1.5% benzyl alcohol, pH 6.8.

No pre-treatment.

3 mM histidine, 1.5% 6.84/6.92 12.9 100 benzyl alcohol, pH 6.8

3 mM Na2HP04, 1.5% 6.83/6.86 15.9 123 benzyl alcohol, pH 6.8

#Desamido content corrected by 1% per 0.1 pH unit deviation from 6.8.

From the above table it appears that the deamidation rate of hGH is reduced to 84% relative to the histidine (68% relative to the phosphate formulation) when the hGH solution is treated with Zn++ in the presence of Ca++ or lysine prior to resalting into the final histidine formulation. REFERENCES

1) Y.-C.J. Wang and M.A. Hanson. Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers. J. Parenteral Science and Technology 42 (Suppl.) (1988) 53-525.

2) M.C. Manning, K. Patel, R.T. Borchardt. Stability of Protein Pharmaceuticals. Pharmaceutical Research 6 (11) (1989) 903-918.

3) B.A. Johnson, J.M. Shirokawa, W.S. Hancock, M.W. Spellman, L.J. Basa and D.W. Asward. J.Biol.Chem. 264, 1462-71 (1989) .

4) L.C. Teh et al., J.Biol.Chem., 262, 785-794 (1987) .

5) G.W. Becker et al.. Biotech.Appl.Biochem. , 10, 326- 337 (1988) .

6) R.A. Houghten et al. , Arch.Biochem.Biophys. , 178, 350-355 (1977) .

7) R.M. Riggin et al., Anal.Biochem. , 167, 199-209 (1987) .

8) P. Gellerfors et al., Acta Paediatr.Scand (suppl), 370, 93-100 (1990) .

9) M.J. Kaufman, Pharm.Res., 7 (3) 289-292 (1990) .

Citas de patentes
Patente citada Fecha de presentación Fecha de publicación Solicitante Título
WO1992017200A2 *25 Mar 199215 Oct 1992Genentech, Inc.Stable growth hormone metal ion formulations
US4816568 *16 May 198628 Mar 1989International Minerals & Chemical Corp.Stabilization of growth hormones
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WO1998027980A2 *18 Dic 19972 Jul 1998Takeda Chemical Industries, Ltd.Method of producing a sustained-release preparation
WO1998027980A3 *18 Dic 199713 Ago 1998Takeda Chemical Industries LtdMethod of producing a sustained-release preparation
WO2008067223A220 Nov 20075 Jun 2008Genentech, Inc.Il-17a/f heterodimeric polypeptides and therapeutic uses thereof
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WO2011119487A221 Mar 201129 Sep 2011Genentech, Inc.Compositions and methods useful for stabilizing protein-containing formulations
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WO2012045274A18 Oct 201112 Abr 2012Shanghai Kexin Biotech Co., Ltd.Moesin modulators and uses thereof
WO2012045281A18 Oct 201112 Abr 2012Shanghai Kexin Biotech Co., Ltd.Diagnostic and therapeutic uses of moesin fragments
WO2012092539A230 Dic 20115 Jul 2012Takeda Pharmaceutical Company LimitedAntibodies to dll4 and uses thereof
WO2013096516A119 Dic 201227 Jun 2013Xoma Technology Ltd.Methods for treating acne
WO2013106489A19 Ene 201318 Jul 2013The Scripps Research InstituteHumanized antibodies with ultralong cdr3s
WO2015010100A218 Jul 201422 Ene 2015Fabrus, Inc.Humanized antibodies with ultralong complementarity determining regions
WO2015017146A218 Jul 20145 Feb 2015Fabrus, Inc.Antibodies with ultralong complementarity determining regions
WO2016126153A122 Dic 201511 Ago 2016Stichting Vu-VumcWound healing formulation
WO2016140910A229 Feb 20169 Sep 2016University Of RochesterCompositions and methods of using anti-mullerian hormone for treatment of infertility
EP0905143A2 *21 Sep 199831 Mar 1999Takeda Chemical Industries, Ltd.Complex of human growth hormone and zinc and use
EP0905143A3 *21 Sep 19986 Sep 2000Takeda Chemical Industries, Ltd.Complex of human growth hormone and zinc and use
EP1666596A11 Jun 20017 Jun 2006Genentech, Inc.Secreted and transmembrane polypeptides and nucleic acids encoding the same
EP1897944A220 Dic 200012 Mar 2008Genentech, Inc.IL-17 homologous polypeptides and therapeutic uses thereof
EP1944317A229 Ago 200116 Jul 2008Genentech, Inc.Secreted and transmembrane polypeptides and nucleic acids encoding the same
EP1953173A122 May 20006 Ago 2008Genentech, Inc.Secreted and transmembrane polypeptides and nucleic acids endoding the same
EP1956030A122 May 200013 Ago 2008Genentech, Inc.Secreted and transmembrane polypeptides and nucleic acids endoding the same
EP1978029A222 May 20008 Oct 2008Genentech, Inc.Secreted and transmembrane polypeptides and nucleic acids endoding the same
EP1995321A218 Jul 200626 Nov 2008Genentech, Inc.Gene disruptions, compositions and methods relating thereto
EP2002714A116 Nov 200617 Dic 2008Genentech, Inc.Novel gene disruptions, compositions and methods relating thereto
EP2014298A230 May 200114 Ene 2009Genentech, Inc.Interleukin-22 polypeptides, nucleic acids encoding the same and methods for the treatment of pancreatic disorders
EP2049148B1 *6 Jul 200628 Sep 2016Daewoong Co., Ltd.A stable liquid formulation of human growth hormone
EP2050335A19 Feb 200722 Abr 2009Genentech, Inc.Gene disruptions, compositions and methods relating thereto
EP2050762A28 Mar 199922 Abr 2009Genentech, Inc.Novel polypeptides and nucleic acids encoding the same
EP2075254A130 Mar 20051 Jul 2009NsGene A/STherapeutic use of a growth factor, NsG33
EP2075334A122 Jun 20011 Jul 2009Genentech, Inc.EG-VEGF nucleic acids and polypeptides and methods of use
EP2082645A118 Abr 200729 Jul 2009Genentech, Inc.Novel gene disruptions, compositions and methods relating thereto
EP2093570A14 Jun 200426 Ago 2009Genentech, Inc.Modulating the interaction between HGF beta chain and c-met
EP2110434A124 Feb 200321 Oct 2009Genentech, Inc.Type-1 cytokine receptor GLM-R
EP2163562A221 Jun 200617 Mar 2010XOMA Technology Ltd.IL-1beta binding antibodies and fragments thereof
EP2186402A118 May 200619 May 2010Genentech, Inc.Knock-out animal models for novel genes and methods of use
EP2228446A11 Dic 200015 Sep 2010Genentech, Inc.Secreted and transmembrane polypeptieds and nucleic acids encoding the same
EP2258848A120 Dic 20008 Dic 2010Genentech, Inc.Il-17 homologous polypeptide and therapeutic uses thereof
EP2277908A22 Jun 200426 Ene 2011Genentech, Inc.IL-17A/F heterologous polypeptides, antibodies and therapeutic uses thereof
EP2289911A230 Mar 20052 Mar 2011NsGene A/STherapeutic use of a growth factor, NsG33
EP2290081A220 Dic 20002 Mar 2011Genentech, Inc.IL-17 homologous polypeptide and therapeutic uses thereof
EP2314623A121 Jun 200627 Abr 2011XOMA Technology Ltd.IL-1beta binding antibodies and fragments thereof
EP2333069A214 May 199915 Jun 2011Genentech, Inc.Therapeutic uses of IL-17 homologous polypeptides
EP2335725A129 Mar 200422 Jun 2011Genentech, Inc.High concentration antibody and protein formulations
EP2336164A119 Dic 200622 Jun 2011Genentech, Inc.Recombinant production of heparin binding proteins
EP2336178A110 Dic 200422 Jun 2011Genentech, Inc.Methods and compositions for inhibiting C-Met dimerization and activation
EP2343551A19 Abr 200713 Jul 2011Genentech, Inc.Disheveled PDZ modulators
EP2360248A117 Ago 200624 Ago 2011The Rockefeller UniversityPly-GBS mutant lysins
EP2389946A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2389947A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2389948A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2389949A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2389950A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2389951A122 Mar 200730 Nov 2011Novartis AGAnti-tumor cell antigen antibody therapeutics
EP2446894A227 Oct 20052 May 2012University Of DenverAdrenocorticotropic hormone analogs and related methods
EP2450050A120 Nov 20079 May 2012Genentech, Inc.IL-17A/F heterodimeric polypeptides and therapeutic uses thereof
EP2784084A12 Jun 20041 Oct 2014Genentech, Inc.IL-17 A/F heterologous polypeptides and therapeutics uses thereof
EP2805964A121 Dic 201026 Nov 2014Ambrx, Inc.Modified bovine somatotropin polypeptides and their uses
EP2805965A121 Dic 201026 Nov 2014Ambrx, Inc.Modified porcine somatotropin polypeptides and their uses
EP2851373A118 Dic 200825 Mar 2015Xoma (Us) LlcMethods for the treatment of gout
EP3050900A119 Dic 20123 Ago 2016Xoma (Us) LlcMethods for treating acne
EP3056511A221 Jun 200617 Ago 2016Xoma (Us) LlcIl-1beta binding antibodies and fragments thereof
EP3091029A130 Oct 20129 Nov 2016F. Hoffmann-La Roche AGAnti-il13 antibody formulations
EP3112468A114 May 19994 Ene 2017Genentech, Inc.Il-17 homologous polypeptides and therapeutic uses thereof
EP3124045A220 Dic 20071 Feb 2017Xoma (Us) LlcTreatment of il-1 beta related diseases
EP3178492A129 Mar 200414 Jun 2017Genentech, Inc.High concentration antibody and protein formulations
EP3181147A120 Nov 200721 Jun 2017Genentech, Inc.Il-17a/f heterodimeric polypeptides and therapeutic thereof
US619110711 Sep 199820 Feb 2001Takeda Chemical Industries, Ltd.Complex of human growth hormone and zinc
US619735018 Dic 19976 Mar 2001Takeda Chemical Industries, Ltd.Method of producing a sustained-release preparation
US639910314 Nov 20004 Jun 2002Takeda Chemical Industries, Inc.Method of producing a sustained-release preparation
US642929623 Ene 20016 Ago 2002Takeda Chemical Industries, Ltd.Complex of human growth hormone and zinc and use
US65694067 Ago 200127 May 2003Nektar TherapeuticsInhaleable spray dried 4-helix bundle protein powders having minimized aggregation
US666423428 Jun 200116 Dic 2003Monsanto Technology LlcNon-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin
US66735801 Jun 20016 Ene 2004Genentech, Inc.Identification and modification of immunodominant epitopes in polypeptides
US671999021 Feb 200113 Abr 2004Monsanto Technology LlcNon-aqueous injectable formulations for extended release of somatotropin
US671999226 Jun 200113 Abr 2004Monsanto Technology LlcNon-aqueous surfactant-containing formulations for extended release of somatotropin
US683807514 Mar 20034 Ene 2005Nektar TherapeuticsInhaleable spray dried 4-helix bundle protein powders having minimized aggregation
US703009122 Oct 200318 Abr 2006Monsanto Technology LlcNon-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin
US70375164 Mar 20042 May 2006Monsanto Technology LlcNon-aqueous surfactant-containing formulations for extended release of somatotropin
US70489384 Mar 200423 May 2006Monsanto Technology LlcNon-aqueous injectable formulations for extended release of somatotropin
US717311511 Ene 20016 Feb 2007Genentech, Inc.Stra6 polypeptides
US723563313 Nov 200226 Jun 2007Genentech, Inc.Cytokine receptors and nucleic acids encoding the same
US726811217 Dic 200311 Sep 2007Genetech, Inc.Use of insulin for the treatment of cartilaginous disorders
US74562512 Feb 200725 Nov 2008Trimeris, Inc.HIV fusion inhibitor peptides with improved biological properties
US748199714 Feb 200527 Ene 2009Montana State UniversitySnow mountain virus genome sequence, virus-like particles and methods of use
US758229124 May 20061 Sep 2009The Rockefeller UniversityBacteriophage lysins for Enterococcus faecalis, Enterococcus faecium and other bacteria
US774143922 May 200622 Jun 2010Genentech, Inc.Isolated stra6 polypeptides
US785527831 Oct 200721 Dic 2010Genentech, Inc.Antibodies to Stra6 polypeptides
US793965018 Jul 200610 May 2011Genentech, Inc.Stra6 polypeptides
US803489920 Oct 200811 Oct 2011Trimeris, Inc.HIV fusion inhibitor peptides with improved biological properties
US810558517 Ago 200631 Ene 2012The Rockefeller UniverstiyPly-GBS mutant lysins
US838946931 May 20065 Mar 2013The Rockefeller UniversityBacteriophage lysins for Bacillus anthracis
US853591215 Oct 201017 Sep 2013Genentech, Inc.Chimeric fibroblast growth factors with altered receptor specificity
US8748573 *5 Ago 201010 Jun 2014Ironwood Pharmaceuticals, Inc.Formulations comprising linaclotide
US880262814 Ago 200912 Ago 2014Ironwood Pharmaceuticals, Inc.Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
US893303017 Feb 201113 Ene 2015Ironwwod Pharmaceuticals, Inc.Treatments for gastrointestinal disorders
US966239521 Sep 201230 May 2017Genentech, Inc.Compositions and methods useful for stabilizing protein-containing formulations
US970837117 Ago 201218 Jul 2017Ironwood Pharmaceuticals, Inc.Treatments for gastrointestinal disorders
US97967847 Jul 201424 Oct 2017Beth Israel Deaconess Medical Center, Inc.Methods and compositions for the generation and use of conformation-specific antibodies
US20110059903 *5 Ago 201010 Mar 2011Ironwood Pharmaceuticals, Inc.Formulations Comprising Linaclotide
US20120009225 *14 Ago 200912 Ene 2012Ironwood Pharmaceuticals, Inc.Stable Solid Formulation of Therapeutic Polypeptides Suitable for Oral Administration
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Clasificación internacionalA61K47/02, A61K47/18, A61K9/19, A61K38/27
Clasificación cooperativaA61K38/27, A61K9/19, A61K47/02, A61K47/183
Clasificación europeaA61K47/02, A61K47/18B, A61K38/27, A61K9/19
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