EP2451471A1 - Langsamwirkende insulinzubereitungen - Google Patents

Langsamwirkende insulinzubereitungen

Info

Publication number
EP2451471A1
EP2451471A1 EP10726993A EP10726993A EP2451471A1 EP 2451471 A1 EP2451471 A1 EP 2451471A1 EP 10726993 A EP10726993 A EP 10726993A EP 10726993 A EP10726993 A EP 10726993A EP 2451471 A1 EP2451471 A1 EP 2451471A1
Authority
EP
European Patent Office
Prior art keywords
arg
pro
asp
lys
glu
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Withdrawn
Application number
EP10726993A
Other languages
German (de)
English (en)
French (fr)
Inventor
Isabell Schoettle
Christiane Fuerst
Verena Siefke-Henzler
Gerrit Hauck
Walter Kamm
Julia Schnieders
Jutta Carls
Gert Wolf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of EP2451471A1 publication Critical patent/EP2451471A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to an aqueous pharmaceutical formulation with a
  • Type II diabetes is not generally deficient in insulin, but in a large number of cases, especially in advanced stages, treatment with insulin may be indicated
  • the replacement of the body's insulin secretion by exogenous, usually subcutaneous administration of insulin generally does not approach the above-described quality of the physiological regulation of blood glucose.
  • derailments of blood glucose go up or down, which in their most severe forms can be life-threatening could be.
  • increased blood glucose levels without initial symptoms represent a considerable health risk over years.
  • the large-scale DCCT study in the USA The Diabetes Control and Compounds Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) showed clearly that chronically elevated blood glucose levels are significantly responsible for the development of late diabetic damage. Diabetic late damage is microvascular and macrovascular
  • Insulin preparations are achieved. Fast-acting formulations are given at meal times to compensate for the postprandial increase in blood glucose. Slow-acting basal insulins should ensure the basic supply of insulin, especially at night, without leading to hypoglycaemia.
  • Insulin is a 51 amino acid polypeptide distributed among 2 amino acid chains: the 21 amino acid A chain and the 30 amino acid B chain. The chains are linked by 2 disulfide bridges. Insulin preparations have been used for diabetes therapy for many years. Not only naturally occurring insulins are used, but more recently also insulin derivatives and analogues.
  • Insulin analogs are analogues of naturally occurring insulins, viz
  • Human insulin or animal insulins which differ in substitution of at least one naturally occurring amino acid residue with other amino acids and / or addition / removal of at least one amino acid residue from the corresponding otherwise identical naturally occurring insulin. These may also be amino acids that are not naturally occurring.
  • Insulin derivatives are derivatives of naturally occurring insulin or a
  • Insulin analog obtained by chemical modification.
  • the chemical modification may e.g. in the addition of one or more particular chemical groups to one or more amino acids.
  • insulin derivatives and insulin analogues have a slightly altered effect on human insulin.
  • EP 0 375 437 and EP 0 678 522 EP 0 124 826 relates inter alia. on substitutions of B27 and B28.
  • EP 0 678 522 describes insulin analogues which have different amino acids in position B29, preferably proline, but not glutamic acid.
  • EP 0 375 437 comprises insulin analogues with lysine or arginine in B28, which may optionally be additionally modified in B3 and / or A21.
  • Protected modifications are modified in the asparagine in B3 and at least one other amino acid in positions A5, A15, A18 or A21.
  • insulin derivatives and insulin analogues have a slightly altered effect on human insulin.
  • insulin analogs are described in which at least one amino acid of positions B1-B6 is replaced by lysine or arginine. Such insulins have a prolonged action according to WO 92/00321.
  • the insulin analogues described in EP-A 0 368 187 also have a delayed action.
  • the concept of intensified insulin therapy seeks to reduce the health risk by aiming for a stable control of blood sugar levels by early administration of basal insulin.
  • the insulin preparations on the market of naturally occurring insulin for insulin substitution differ in the source of insulin (e.g., beef, pork, human insulin) and the composition with which the profile of action (onset and duration of action) can be affected.
  • Insulins include insulin glargine (Gly (A21) Arg (B31) Arg (B32) human insulin) with a prolonged duration of action. Insulin glargine is injected as an acidic, clear solution and due to its solubility properties it falls in the physiological pH range of the
  • Insulin glargine is injected once daily and is distinguished from other long-acting insulins by its low serum profile and the associated reduction in the risk of nocturnal hypoglycemia (Schubert-Zsilavecz et al., 2: 125-130 (2001)).
  • the specific preparation of insulin glargine, which leads to the prolonged duration of action, is in
  • the B chain end consists of an amidated basic amino acid residue such as lysine or argininamide, i. in the amidated basic amino acid residue at the B chain end, the carboxyl group of the terminal amino acid is in its amidated form, and
  • the N-terminal amino acid residue of the insulin A chain is a lysine or arginine residue
  • the amino acid position A21 is occupied by a glycine residue
  • An object of the invention is therefore an aqueous pharmaceutical
  • a further subject of the invention is a pharmaceutical formulation as described above, in which the insulin analogue is selected from a group comprising:
  • Another object of the invention is a pharmaceutical formulation as described above, wherein the isotonizing agent is selected from a group containing mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol.
  • Another object of the invention is a pharmaceutical formulation as described above, having a pH in the range of pH 2.5 to 4.5, preferably in the range of pH 3.0 to 4.0, particularly preferably in the range of pH. 3 , 75th
  • Another object of the invention is a pharmaceutical formulation as described above, wherein the insulin, the insulin analogue and / or the insulin derivative is present in a concentration of 60-6000 nmol / ml
  • a further subject of the invention is a pharmaceutical formulation as described above in which glycerol is present in a concentration of 20 to 30 mg / ml, preferably in a concentration of 25 mg / ml.
  • a further subject of the invention is a pharmaceutical formulation as described above in which m-cresol is present in a concentration of 1 to 3 mg / ml, preferably in a concentration of 2 mg / ml.
  • Another object of the invention is a pharmaceutical formulation as described above in which zinc is present in a concentration of 0.01 or 0.03 or 0.08 mg / ml.
  • a further subject of the invention is a pharmaceutical formulation as described above, which additionally contains a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, or exendin-3 or -4 or an analogue or derivative thereof ,
  • GLP1 glucagon-like peptide-1
  • Another object of the invention is a pharmaceutical formulation as described above, which additionally contains exendin-4.
  • Another object of the invention is a pharmaceutical formulation as described above in which an analog of exendin-4 is selected from a group containing
  • Another object of the invention is a pharmaceutical formulation as described above in which an analog of exendin-4 is selected from a group containing
  • Another object of the invention is a pharmaceutical formulation as described above, in which the peptide -LySo-NH 2 is added to the C-termini of the analogues of exendin-4.
  • Another object of the invention is a pharmaceutical formulation as described above in which an analog of exendin-4 is selected from a group containing
  • Another object of the invention is a pharmaceutical formulation as described above, in which in addition Arg 34 , Lys 26 (N ⁇ ( ⁇ -glutamyl (N ⁇ -hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof is included.
  • Another object of the invention is a pharmaceutical formulation as described above, in which the amino acid methionine is present, preferably in the concentration range of up to 10 mg / ml, more preferably of up to 3 mg / ml.
  • Another object of the invention is a method for producing a
  • Another object of the invention is a use of a formulation as described above for the treatment of diabetes mellitus.
  • Another object of the invention is a medicament for the treatment of
  • Diabetes mellitus consisting of a formulation as described above.
  • the preparation may further contain preservatives (e.g., phenol, cresol,
  • isotonizing agents e.g., mannitol, sorbitoi, lactose, dextrose,
  • Trehalose, sodium chloride, glycerol Buffer substances, salts, acids and alkalis and other excipients. These substances may be present individually or as mixtures.
  • Giycerol, dextrose, lactose, sorbitoi and mannitol are usually present in the pharmaceutical preparation in a concentration of 100-250 mM, NaCl in a concentration up to 150 mM.
  • Buffer substances e.g. Phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e., 2-amino-2-hydroxymethyl-1, 3, -
  • Propandiol buffers and corresponding salts may be present in a concentration of 5-250 mM, preferably 10-100 mM.
  • Other excipients may include salts or arginine.
  • a further subject of the invention is a pharmaceutical formulation as described above in which the insulin analogue is in a concentration of 60-6000 nmol / ml (this corresponds approximately to a concentration of 0.35-70 mg / ml or 10-1000 Units / ml), preferably in a concentration of 240-3000 nmol / ml (this corresponds approximately to a concentration of 1.4-35 mg / ml or 40-500
  • the surfactant is present in a concentration of 5-200 ⁇ g / ml, preferably of 5-120 ⁇ g / ml and more preferably of 20-75 ⁇ g / ml.
  • Another object of the invention is a pharmaceutical formulation as stated above, in which glycerol and / or mannitol in a concentration of 100-250 mM, and / or NaCl preferably in a concentration up to 150 mM.
  • Another object of the invention is a pharmaceutical formulation as stated above, in which a buffer substance in a concentration of 5 - 250 mM is present.
  • Another object of the invention is a pharmaceutical insulin formulation, the further additives such. Contains salts which retard the release of insulin. Also mixtures of such sustained-release insulins described above
  • Formulations are included. Another object of the invention is a method for producing such pharmaceutical formulations. Likewise, another object of the invention is the use of such formulations for the treatment of diabetes mellitus.
  • Another object of the invention is the use or the addition of surfactants as a stabilizer during the production process of insulin,
  • Insulin analogues or insulin derivatives or their preparations are insulin analogues or insulin derivatives or their preparations.
  • Fig. 1 Hypoglycemic effect of new insulin analogues according to formula I in
  • Fig. 2 blood sugar lowering effect of new insulin analogues according to formula I in
  • Fig. 3 Hypoglycemic effect of YKL205 in the dog
  • Fig. 4 Zinc dependence of the hypoglycemic effect of YKL205 in the dog
  • the solution is prepared by adding about 25% water for injection.
  • One after the other are SAR161271 and the zinc chloride
  • the tonicity agent Glyceroi in the concentration 2.5% was selected.
  • the formulation is more stable compared to 0.8% NaCl as a tonicity agent.
  • precipitation was detected using NaCl during the preparation which was insoluble.
  • the osmolarity was 290 ⁇ 30 m ⁇ smol / kg for both substances.
  • m-cresol was chosen as a preservative. The concentration of 2 mg / ml was chosen, although 1.5 mg / ml would have been sufficient for preservation. Nevertheless, the higher m-cresol concentration was chosen due to microbiological safety aspects and specification specification. In addition, the formulations (except 2.1 mg / ml m-cresol) were placed on stability (3 months).
  • Example 4 Formulation of the amidated insulin derivatives
  • Examples 4 to 8 serve only to determine the biological, pharmacological and physicochemical properties of insulin analogues according to formula I by firstly providing formulations thereof (example 4) and then carrying out corresponding tests (examples 5 to 8).
  • a solution was prepared of the compounds as follows: The insulin analog according to the invention was dissolved at a target concentration of 240 ⁇ 5 ⁇ M in 1 mM hydrochloric acid with 80 ⁇ g / ml zinc (as zinc chloride).
  • compositions were used as solvent medium:
  • freeze-dried material was first about a 30% higher amount than due to the molecular weight and the desired
  • Target concentration of 240 ⁇ 5 ⁇ M the final solution was syringed with a 0.2 ⁇ m filter attachment into a with a septum and a crimp cap
  • Example 5 Evaluation of the hypoglycemic effect of new insulin analogues in the rat
  • the hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic Wistar rats.
  • Male rats are injected subcutaneously with a dose of 9 nmol / kg of an insulin analogue.
  • blood samples are taken from the animals and the blood sugar content is determined therein. The experiment clearly shows (see Fig. 1) that the insulin analog used according to the invention significantly delayed
  • Example 6 Evaluation of the hypoglycaemic effect of new insulin analogues in the dog
  • the hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic beagle dogs.
  • Male animals are injected subcutaneously with a dose of 6 nmol / kg of an insulin analogue.
  • blood samples are taken from the animals and the blood sugar content is determined therein.
  • the experiment clearly shows (see Fig. 2) that the insulin analog according to the invention used is a clear one
  • the hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic beagle dogs.
  • Male animals are injected subcutaneously with a dose of 6 nmol / kg and 12 nmol / kg of an insulin analogue.
  • blood samples are taken from the animals and the blood sugar content is determined therein.
  • Example 8 Evaluation of the hypoglycemic effect in dogs at different zinc concentrations in the formulation
  • FIG. 4 shows the result. Thereafter, the time-effect curve of the insulin analog according to the invention by the content of zinc ions in the formulation at the same concentration of insulin influence in such a way that at zero or low zinc content observed a rapid onset and the effect persists over 24 hours, while at higher zinc content low onset of action is observed and the insulin action persists well longer than 24 hours.
  • Example 9 The insulin analog according to the invention was dissolved at a target concentration of 240 + 5 ⁇ M in 1 mM hydrochloric acid with 80 ⁇ g / ml zinc (as zinc chloride).
  • a target concentration 240 + 5 ⁇ M in 1 mM hydrochloric acid with 80 ⁇ g / ml zinc (as zinc chloride).
  • the freeze-dried material was first weighed about 30% higher amount than required due to the molecular weight and the desired concentration. Thereafter, the present concentration was determined by means of analytical HPLC and the solution was then filled to the required volume to achieve the target concentration with 5 mM hydrochloric acid with 80 ug / mL zinc. If necessary, the pH was readjusted to 3.5 + 0.1.
  • the final solution was transferred via syringe with a 0.2 ⁇ m filter attachment to a sterile vial sealed with a septum and crimp cap.
  • the formulations eg with regard to an addition of isotonic agents, preservatives or buffer substances, was carried out.
  • Example 10 Evaluation of the hypoglycemic effect of novel insulin analogues in the rat
  • the hypoglycemic effect of selected new insulin analogs is tested in male, normal, normoglycemic Wistar rats.
  • Male rats are injected subcutaneously with a dose of 9 nmol / kg of an insulin analogue.
  • blood samples are taken from the animals and the blood sugar content is determined therein.
  • the experiment clearly shows (compare Fig. 4) that the insulin analog according to the invention leads to a significantly delayed onset of action and a longer, uniform duration of action.
  • Example 11 Evaluation of the hypoglycemic effect of new insulin analogues in the dog The hypoglycemic effect of selected new insulin analogues is tested in male, healthy, normoglycemic beagle dogs. Male animals are injected subcutaneously with a dose of 6 nmol / kg of an insulin analogue. Immediately before injecting the insulin analogue and at regular intervals up to forty-eight hours after the injection, blood samples are taken from the animals and the blood sugar content is determined therein. The experiment clearly shows that the insulin analog according to the invention leads to a markedly delayed, shallow onset of action and a longer, uniform duration of action.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Genetics & Genomics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
EP10726993A 2009-07-06 2010-07-02 Langsamwirkende insulinzubereitungen Withdrawn EP2451471A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102009031750 2009-07-06
DE102010013133 2010-03-27
PCT/EP2010/059438 WO2011003823A1 (de) 2009-07-06 2010-07-02 Langsamwirkende insulinzubereitungen

Publications (1)

Publication Number Publication Date
EP2451471A1 true EP2451471A1 (de) 2012-05-16

Family

ID=43428815

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10726993A Withdrawn EP2451471A1 (de) 2009-07-06 2010-07-02 Langsamwirkende insulinzubereitungen

Country Status (7)

Country Link
US (1) US20120232002A1 (enExample)
EP (1) EP2451471A1 (enExample)
JP (1) JP5675799B2 (enExample)
AR (1) AR077455A1 (enExample)
TW (1) TW201113032A (enExample)
UY (1) UY32765A (enExample)
WO (1) WO2011003823A1 (enExample)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009203809B2 (en) 2008-01-09 2013-07-25 Sanofi-Aventis Deutschland Gmbh Novel insulin derivatives having an extremely delayed time-action profile
HUE068164T2 (hu) 2008-10-17 2024-12-28 Sanofi Aventis Deutschland Egy inzulin és egy GLP-1 agonista kombinációja
WO2011003822A2 (de) * 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Insulinzubereitungen enthaltend methionin
CA2780460C (en) * 2009-11-13 2018-09-04 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
SG10201500871TA (en) 2009-11-13 2015-04-29 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist and methionine
RS55378B1 (sr) 2010-08-30 2017-03-31 Sanofi Aventis Deutschland Upotreba ave0010 za proizvodnju leka za tretman diabetes mellitus tipa 2
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
BR112014004726A2 (pt) 2011-08-29 2017-04-04 Sanofi Aventis Deutschland combinação farmacêutica para uso no controle glicêmico em pacientes de diabetes tipo 2
TWI559929B (en) 2011-09-01 2016-12-01 Sanofi Aventis Deutschland Pharmaceutical composition for use in the treatment of a neurodegenerative disease
TWI641381B (zh) 2013-02-04 2018-11-21 法商賽諾菲公司 胰島素類似物及／或胰島素衍生物之穩定化醫藥調配物
WO2015104311A1 (en) 2014-01-09 2015-07-16 Sanofi Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives
EP3091995B1 (en) 2014-01-09 2024-03-20 Sanofi Stabilized pharmaceutical formulations of insulin aspart
SG11201604706TA (en) 2014-01-09 2016-07-28 Sanofi Sa Stabilized pharmaceutical formulations of insulin aspart
WO2016001862A1 (en) 2014-07-04 2016-01-07 Wockhardt Limited Extended release formulations of insulins
TWI758239B (zh) 2014-12-12 2022-03-21 德商賽諾菲阿凡提斯德意志有限公司 甘精胰島素/利司那肽固定比率配製劑
TWI748945B (zh) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患治療
TW201705975A (zh) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患之治療

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See also references of WO2011003823A1 *

Also Published As

Publication number Publication date
JP2012532179A (ja) 2012-12-13
JP5675799B2 (ja) 2015-02-25
US20120232002A1 (en) 2012-09-13
UY32765A (es) 2011-01-31
WO2011003823A1 (de) 2011-01-13
TW201113032A (en) 2011-04-16
AR077455A1 (es) 2011-08-31

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