 liquid pharmaceutical composition comprising a glp-1 agonist and methionine and use thereof
专利摘要:
LIQUID PHARMACEUTICAL COMPOSITION UNDERSTANDING A GLP-1 AGONIST AND METHIONIN, USE OF THIS AND METHOD FOR MANUFACTURING THE SAME. The present invention relates to a liquid composition comprising a GLP-1e agonist / / or a pharmacologically tolerable salt thereof and, optionally, at least one pharmaceutically acceptable excipient, wherein the composition comprises methionine, as complementary therapy with metformin and / or with long-acting insulin / insulin derivatives where appropriate. 公开号:BR112012011403B1 申请号:R112012011403-4 申请日:2010-11-11 公开日:2020-12-01 发明作者:Anette Brunner-Schwarz；Werner Müller；Verena Siefke-Henzler 申请人:Sanofi-Aventis Deutschland Gmbh； IPC主号:
专利说明:
[0001] The present application relates to a liquid composition comprising a GLP-1 agonist and / or a pharmacologically tolerable salt thereof and, optionally, at least one pharmaceutically acceptable excipients, where a composition comprises methionine. [0002] The present application also relates to the composition according to the present invention for the treatment of diabetes mellitus. The present application further relates to the use of a composition according to the present invention in the manufacture of a medicament for the treatment of diabetes mellitus. The present application further relates to a method for making a composition according to the present invention, comprising formulation of a GLP-1 agonist and / or a pharmacologically tolerable salt thereof with methionine and, optionally, at least some pharmaceutically excipients acceptable. The present application further relates to a method for treating a patient with a composition according to the present invention, comprising administering a composition to the patient. [0003] Usual compositions of GLP-1 compounds comprise a modifying tonicity, a pH adjustment buffer, and a preservative. [0004] WO 2001/04156 (Pharmaceuticals Zealand) describes a liquid composition of Ser39-exendin-4 (1-39) -NH2), sodium dihydrogen phosphate, and preservatives. [0005] WO 2004/035623 (Pharmaceuticals Zealand) describes a liquid composition comprising a stabilized exendin, 50 mM histidine, 100 to 200 mM sucrose, mannitol or other acceptable sugar, 20 mM methionine, 20 mM asparagine-glutamine or Asp, at a pH of 5.3. Stabilization is effected by certain modifications to the amino acid construct of exendin-4 blocks (1-39), for example, at positions Gln13, Met14, Trp25, or Asn28. [0006] WO 2005/021022 (Novo Nordisk) describes a liquid composition comprising acetylated GLP-1, phenol as a preservative, mannitol and glycerol as a modifying tonicity, and, optionally, a buffer. [0007] WO 2006/051110 (Novo Nordisk) describes a liquid composition comprising liraglutide (compound GLP-1), poloxamer 188 or poloxamer 407 (Pluronic F-127) as a surfactant, phenol, pro-pilen glycol, and sodium phosphate (pH 7.7). Addition of poloxamer -188 or poloxamer -407 leads to stabilization. [0008] Exendins are a group of peptides that can lower blood glucose concentrations. Exendins have a certain similarity for the GLP-1 sequence (7-36) (53%, Goke et al. J. Biol Chem 268, 19650-55). Exendin-3 and exendin-4 stimulates an increase in cAMP cell production in the acinar cells of the pancreas guinea pig through interaction with exendin receptors (Raufman, 1996, Reg. Peptides 61: 1-18). Exendi-na-3, in contrast to exendin-4, effects of an increase in amylase release in the acinar cells of the pancreas. Exendinas acts as GLP-1 agonists. [0009] Glucagon as peptide 1 (GLP-1) is an endocrine hormone that enhances the insulin response following oral intake of glucose or fat. In general, GLP-1 lower glucagon concentrations, slow gastric emptying, stimulates (pro) insulin synthesis, enhances insulin sensitivity, and stimulates insulin-independent glycogen synthesis (Holst (1999), Curr. Med. Chem 6: 1005, Nauck et al. (1997) Exp Clin Endocrinol Diabetes 105: 187 Lopez-Delgado et al. (1998) Endocrinology 139: 2811). Human GLP-1 has 37 amino acid residues (Heinrich et al., Endocrinol. 115: 2176 (1984), Uttenthal et al., J Clin Endocrinol Metabol (1985) 61: 472). Active fragments of GLP-1 include GLP-1 (7-36) and GLP-1 (7-37). [0010] Exendin-3, exendin-4 and exendin agonists have been proposed for the treatment of diabetes mellitus and prevention of hyperglycemia, reducing gastric motility and gastric emptying (US 5, 424,286 and WO98 / 05351). [0011] Exendin analogs can be characterized through amino acid substitutions and / or C-terminal truncation of the native exendin-4 sequence. Such an analogous exendin is described in WO 99/07404, WO 99/25727, and WO 99/25728. [0012] Synthesis of the solid phase of AVE0010 is described in WO 01/04156 A1. AVE0010 has the sequence: desPro36 exendin-4 (1-39) -Lys6-NH2. This substance is published as SEQ ID NO: 93 in WO 01/04156: HGEGTFTSDLSKQMEEEAVRL-FlEWLKNGGPSSGAPPSKKKK-KK-NH2 (SEQ ID NO: 1) Exendina-4 (39 AS) has the sequence: HGEGTFTSDLSKQMEEEAVRL-FlEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 2) Exendin-3 h has the sequence (J. Bio. Chem., 267, 1992, 7402-7405): H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 SEQ ID NO: 3) GLP-1 has the sequence: HAEGTFTSDVSSYLEGQAAKE-FIAWLVKGR-NH2 (SEQ ID NO: 4) [0013] It is an object of the present invention to increase the stability of liquid formulations comprising a GLP-1 a agonist. More particularly, it is an object of the present invention to improve physical and chemical integrity. We found that this object is achieved through the formulation of the GLP-1 agonist with methionine. [0014] It has been found that methionine is able to increase the storage stability of a composition comprising a GLP-1 agonist such as AVE0010. Methionine does not affect the physical integrity of these compositions. [0015] It has been found that, surprisingly, the addition of methionine is able to improve the storage stability of a composition according to the present invention by reducing the proportion of methionine oxidation products, high molecular weight proteins, and total impurities. These parameters are individually or together, a measure of the chemical integrity of the compositions. [0016] It has also been found that, surprisingly, the biological activity of the compositions according to the present invention is increased by the addition of methionine. [0017] The stability of pharmaceutically active polypeptides can be impaired by several mechanisms. These include pH, temperature, lighting, and the effects of certain components. [0018] A range of customary components of formulations of GLP-1 agonists can be disadvantageous to the chemical and / or physical integrity and storage stability of formulations comprising a GLP-1 agonist. This is, for example, polysorbate 20, polysorbate 80, polo-shamer 188, benzalkonium chloride, and lysine. The compositions according to the present invention are therefore preferably free of these components. [0019] The present invention therefore provides for a liquid composition comprising a GLP-1 agonist and / or a pharmaceutically tolerable salt thereof and, optionally, at least one pharmaceutically acceptable excipient, where a composition comprises methionine. [0020] The composition according to the present invention preferably comprises methionine in an amount ranging from 0.5 mg / ml to 20 mg / ml, more preferably in an amount ranging from 1 mg / ml to 5 mg / ml. Methionine in form D can be used. Likewise, L-form methionine can be used. Likewise, mixtures of form D and form L in any desired proportions can be used. [0021] More particularly, a composition according to the present invention is free of surfactants, such as partial polyolysis and fatty acids esters and ethers of polyhydric alcohols such as those of glycerol and sorbitol. The compositions according to the present invention are more particularly free of partial and fatty acids esters and ethers of glycerol and sorbitol selected from the group consisting of Span®, Tween®, Myrj®, Brij®, Cremophor®. In addition, the compositions according to the present invention are more particularly free of polyolysis selected from the group consisting of polypropylene glycols, Polyethylene glycols, poloxamers, Pluronics, Tetronics. More particularly, a composition according to the present invention is free of at least one substance selected from the group consisting of polysorbate, polysorbate and poloxamer. [0022] More particularly, a composition according to the present invention is substantially free, preferably free, of polysorbate, such as, for example, polysorbate 20. [0023] More particularly, a composition according to the present invention is substantially free, preferably free, of polysorbate 80. [0024] More particularly, a composition according to the present invention is substantially free, preferably free, of poloxamer, such as, for example, poloxamer 188. [0025] More particularly, a composition according to the present invention is substantially free, preferably free, of benzalkonium chloride. [0026] More particularly, a composition according to the present invention is substantially free, preferably free, of histidine. [0027] More particularly, a composition according to the present invention is substantially free, preferably free of EDTA, more particularly sodium EDTA. [0028] The composition according to the present invention can comprise one or more substances that are commonly used for pH buffering (buffering substances). Examples of such buffer substances are acetates, citrate, and phosphate, for example, in amounts up to 5 mg / ml, up to 4 mg / ml, up to 3 mg / ml, or up to 2 mg / ml. [0029] The composition according to the present invention can also be substantially free of buffer substances. Likewise, a composition according to the present invention can be free of buffer substances. [0030] The composition according to the present invention can be substantially free of citrate, acetate, and / or phosphate, or else free of citrate, acetate, and / or phosphate. [0031] More particularly, a composition according to the present invention is substantially free, preferably free, of histidine and sodium ED-TA. [0032] More particularly, no insulin is present in a composition according to the present invention. [0033] The pharmaceutical composition of the present invention can have an acidic or physiological pH. An acidic pH range is preferably in the range of pH 1-6.8, pH 3.5-6.8, or pH 3.5-5. A physiological pH is preferably in the range of pH 2.5-8.5, more preferably pH 4.0 to 8.5, even more preferably pH 4.0 to 6.0. Especially preferred is a pH of approximately 4.5. For pH adjustment, physiologically safe diluted acids (typically HCI) and alkali (typically NaOH) are suitable. [0034] The composition according to the present invention can comprise a suitable preservative. Suitable preservatives are, for example, phenol, m-cresol, benzyl alcohol, and / or p-hydroxybenzoate esters. m-Cresol is preferred. [0035] In addition, a composition according to the present invention can comprise suitable modifying tonicities. Suitable modifying tonicities are, for example, glycerol, dextrose, lactose, sorbitol, mannitol, glucose, NaCI, calcium or magnesium compounds such as CaCl2 etc. The concentrations of glycerol, dextsubiu, lactose, sorbitol, mannitol, and glucose are usually in the range of 100-250 mM, NaCI in a concentration of up to 150 mM. Glycerol is preferred. [0036] More particularly, a composition is intended for parenteral administration. A composition according to the present invention is preferably an injectable composition, more preferably for subcutaneous injection. More particularly, a composition of the present invention is suitable for injection once a day. [0037] More particularly, the formulation according to the present invention has, after storage for 1 month, 2 months, 4 months, or 6 months at a temperature of + 5 ° C or 25 ° C, an activity of at least 80%, at least 90%, at least 95%, or at least 98% of activity at the start of storage. [0038] In the present application, "activity" means activity of the GLP-1 agonist that is used in the formulation according to the present invention. Methods for determining the activity of a GLP-1 agonist are known to a person skilled in the art. [0039] Preferably, a composition according to the present invention has a biological activity of GLP-1 agonist of at least 89% or at least 90% after storage for 6 months at 25 ° C. A composition according to the present invention preferably has a biological activity of GLP-1 agonist of at least 45% or at least 50% after storage for 6 months at 40 ° C. [0040] More particularly, the formulation according to the present invention exhibits chemical integrity after storage for 1 month, 2 months, 3 months, 4 months, or 6 months. Chemical integrity means, more particularly, that after storage at a temperature of + 5 ° C, 25 ° C, or 40 ° C the formulation comprises at least 80%, at least 90%, at least 95%, or at least 98% of the active substance, compared with the beginning of storage, in a substantially unchanged form. [0041] Chemical integrity can mean the chemical integrity of the GLP-1 a-gonist. GLP-1 agonists can comprise a methionine residue (for example, position 14 in AVE0010). Chemical integrity of the GLP-1 agonist means, more particularly, that oxidation of the methionine residue is prevented. Here, chemical integrity means, more particularly, that the proportion of oxidized methionine with respect to the entire methionine content of the GLP-1 agonist after storage for 1, 2, 3, 4, or 6 months is below 0, 7%, below 0.6%, below 0.5%, below 0.4%, or below 0.3%. Storage can be carried out, for example, at 5 ° C, 25 ° C, or 40 ° C. Storage for 6 months at 5 ° C is preferred, in which case the proportion of oxidized methionine is below 0.3%. Likewise, storage for 6 months at 25 ° C is preferred, in which case the proportion of oxidized methionine is below 0.7%, below 0.6%, below 0.5%, below 0.4%, or below 0.3%. Likewise, storage for 6 months at 40 ° C is preferred, in which case the proportion of oxidized methionine is below 1%, below 0.7%, below 0.6%, below 0.5%, below 0.4%, or below 0.3%. [0042] Chemical integrity can mean a very low proportion of total impurities in the formulation according to the present invention. The proportion of total impurities with respect to the entire mass of the GLP-1 agonist present in the formulation after storage for 6 months at 40 ° C is more particularly below 50%, below 10% after storage at 25 ° C, and / or below 1.8% after storage at 5 ° C. [0043] Chemical integrity can mean a very low proportion of high molecular weight proteins in the formulation according to the present invention. The proportion of high molecular weight proteins with respect to the entire mass of the GLP-1 agonist present in the formulation after storage for 6 months at 40 ° C is more particularly below 5%, below 4%, below 3%, or below 2%. After storage for 6 months at 25 ° C, the proportion of high molecular weight proteins with respect to the entire mass of the GLP-1 agonist present in the formulation is more particularly below 0.8%, below 0.7%, or below 0.6%. [0044] More particularly, the formulation according to the present invention exhibits physical integrity after storage for 1 month, 2 months, 4 months, or 6 months. Physical integrity means, more particularly, that after storage at a temperature of + 5 ° C, 25 ° C, or 40 ° C the formulation comprises at least 80%, at least 90%, at least 95%, or at least 98 % of the active substance, compared to the start of storage, in a substantially unchanged physically form. [0045] Physical integrity can mean the integrity of the GLP-1 agonist. Physical integrity means, more particularly, that the GLP-1 agonist does not form aggregates, such as, for example, fibrils. [0046] The GLP-1 agonist is preferably selected from the group consisting of exendin-3 and analogues and derivatives thereof, exendin-4 and analogues and derivatives thereof, and in which case the GLP-1 agonist is most preferably selected from of the group consisting of AVE0010 and exendin-4. [0047] Exendin-3, exendin-3 analogs and derivatives, exendin-4, and exendin-4 analogs and derivatives can be found in WO 01/04156, WO 98/30231, US 5,424,286, EP application 99 610043.4, and WO 2004/005342. These documents are hereby incorporated by reference. Exendin-3, exendin-4, and analogs and derivatives thereof described in these documents can be synthesized by means of the methods described therein, after which the modifications are optionally carried out. [0048] The sequences of AVE0010 (SEQ ID NO: 1), exendin-4 (SEQ ID NO: 2), and exendin-3 (SEQ ID NO: 3) show a high degree of similarity. The sequences for AVE0010 and exendin-4 are identical at positions 1-37. Sequence 1-39 from exendin-4 is in 37 of the 39 positions (94%) identical to exendin-3 sequence in positions 48-86. With reference to the sequences, a person skilled in the art can easily convert the positions specified here, which refer to a particular sequence (for example, to the sequence of AVE0010 or exendin-4), to other sequences. [0049] Analogs and derivatives of exendin-3 and / or exendin-4 will more particularly contain a modified amino acid sequence. For example, single amino acids can be deleted (for example, desPro36, des-Pro37, desAsp28, desMet (O) 14 in exendin-4 and the corresponding positions in exendin-3). Also, single positions can be substituted (for example, Met (O) 14, Trp (O2) 25, IsoAsp28, Asp28 Pro38 in exendin-4 and the corresponding positions in exendin-3), in which case unnatural amino acids such as Met (O) (methionine sulfoxide or methionine sulfone), Trp (O2) (N-formylkynurenine), and / or IsoAsp (-aspartate or isoaspartate) can also be used. Unnatural amino acids can be easily inserted, in the form of corresponding construction of amino acid blocks, in the sequence. [0050] In addition, the C terminal and / or the N terminal can be modified, for example, by an additional sequence such as - (Lys) -, - (Lys) 2-, - (Lys) 3-, - (Lys ) 4-, - (Lys) 5-, - (Lys) 6-, -Asn- (Glu) 5-, in which case - (Lys) 4-, - (Lys) 5-, - (Lys) 6- , -Asn- (Glu) 5- are preferred. The carboxyl group at the C-terminus is preferably modified to an amide group (-NH2). Optionally, the modification of the C terminal and / or the N terminal is performed as an additional step after completion of the synthesis. [0051] Pharmaceutically tolerable salts can be manufactured in an additional step after completing the synthesis cycles of the method according to the present invention. The manufacture of pharmaceutically tolerable salts of peptides is known to a person skilled in the art. A preferred pharmaceutically tolerable salt is acetate. [0052] The GLP-1 agonist is preferably selected from the group consisting of exendin-4, exendin-4 analogs and derivatives, and pharmaceutically tolerable salts thereof. [0053] An additional preferred GLP-1 agonist is an exendin-4 analogue selected from the group consisting of: H-desPro36-exendin-4-Lys6-NH2, H-des (Pro36,37) -exendin-4-Lys4-NH2, H-des (Pro36,37) -exendin-4-Lys5-NH2 and pharmaceutically tolerable salts thereof. [0054] An additional preferred GLP-1 agonist is an exendi-na-4 analogue selected from the group consisting of: desPro36 [Asp28] exendin-4 (1-39), desPro36 [lsoAsp28] exendina-4 (1-39), desPro36 [Met (O) 14, Asp28] exendin-4 (1-39), desPro36 [Met (O) 14, lsoAsp28] exendin-4 (1-39), desPro36 [Trp (O2) 25, Asp28] exendin-2 (1-39), desPro36 [Trp (O2) 25, lsoAsp28] exendin-2 (1-39), desPro36 [Met (O) 14Trp (O2) 25, Asp28] exendin-4 (1-39), desPro36 [Met (O) 14Trp (O2) 25, lsoAsp28] exendin-4 (1-39) and pharmaceutically tolerable salts thereof. [0055] An additional preferred GLP-1 agonist is an exendin-4 analogue selected from a group as described in the previous paragraph, where the -Lys6-NH2 peptide is attached to the C-terminus of exendin-4 analogs. [0056] An additional preferred GLP-1 agonist is an exendin-4 analogue selected from the group consisting of: H- (Lys) 6-desPro36 [Asp28] exendin-4 (1-39) -Lys6-NH2, desAsp28Pro36, Pro37, Pro38 exendina-4 (1-39) -NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) -NH2, H-Asn- (Glu) 5desPro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) -NH2, desPro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36 [Trp (O2) 25, Asp28] exendin-4 (1-39) -Lys6-NH2, H-desAsp28 Pro36, Pro37, Pro38 [Trp (O2) 25] exendin-4 (1-39) -NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) -NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) -NH2, desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36 [Met (O) 14, Asp28] exendin-4 (1-39) -Lysg-NH2, desMet (O) 14 Asp28 Pro 36, Pro37, Pro38 exendina-4 (1-39) -NH2, H- (Lys) 6-desPro36, Pro 37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2, desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -Lys6-NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39) -Lys6-NH2, desAsp28Pro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25] exendin-4 (1-39) -NH2, H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39) -NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2, desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6-desPro36 Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] exendi-na-4 (1-39) - (Lys) 6-NH2, H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39) - (Lys) 6-NH2 and pharmaceutically tolerable salts thereof . [0057] Likewise, the GLP-1 agonist can be selected from the group consisting of GLP-1 and GLP-1 analogs and derivatives. The preferred additional GLP-1 agonist is selected from the group consisting of Arg34, Lys26 (Nε (γ-glutamyl (Na-hexadecanoyl))) GLP-1 (7-37) [liraglutide] and a pharmacologically tolerable salt thereof. [0058] An additional preferred GLP-1 agonist is AVE0010, AVE0010 has the sequence desPro36 exendin-4 (1-39) -Lysg-NH2 (SEQ ID NO: 1). Likewise, pharmaceutically tolerable salts of AVE0010 are preferred. [0059] The GLP-1 agonist, for example, AVE0010, is more particularly used in an amount ranging from 0.01 mg / ml to 0.5 mg / ml or 0.05 mg / ml to 1.5 mg / ml. [0060] (a) desPro36 exendina-4 (1-39)-Lys6-NH2 (por exemplo, aproximadamente 0,1 mg/mL), (b) tri-hidratado de acetado de sódio (aproximadamente 3.5 mg/mL), (c) m-cresol (aproximadamente 2.7 mg/mL), (d) L-metionina (aproximadamente 3 mg/mL), (e) 85% de glicerol (aproximadamente 18 mg/mL), (f) aproximadamente 0,1 N ácido clorídrico, se ajusta a um pH de aproximadamente 4.5 é exigido, (g) aproximadamente 0,1 N de NaOH solução, se ajusta a um pH de aproximadamente 4,5 é exigido, e (h) água. In a particular embodiment, the formulation according to the present invention comprises the following components: (a) desPro36 exendin-4 (1-39) -Lys6-NH2 (for example, approximately 0.1 mg / ml), (b) sodium acetate trihydrate (approximately 3.5 mg / mL), (c) m-cresol (approximately 2.7 mg / mL), (d) L-methionine (approximately 3 mg / mL), (e) 85% glycerol (approximately 18 mg / mL), (f) approximately 0.1 N hydrochloric acid, adjusts to a pH of approximately 4.5 is required, (g) approximately 0.1 N NaOH solution, adjusts to a pH of approximately 4.5 is required, and (h) water. [0061] More particularly, the formulation according to the present invention consists of the components mentioned in (a) to (h). [0062] In the present application, "approximately" means that the components can be present, for example, within the ranges of ± 10, ± 20, or ± 30% around the values specified in the compositions according to the present invention. [0063] If a composition according to the present invention comprises more than one GLP-1 agonist, then these GLP-1 agonists are selected independently from one another. [0064] The suitable packaging for a composition according to the present invention is, for example, a syringe or a glass container with a suitable closure, from which effective therapeutically individual doses can be withdrawn as needed. Equally suitable are injection pens for administering doses; such pens comprise a container (e.g., a cartridge) that contains a pharmaceutical composition according to the present invention. [0065] The present invention further provides a method for treating a patient with a composition according to the present invention, comprising administering a composition to the patient. [0066] The composition according to the present invention is intended more particularly for the treatment of diabetes mellitus, more particularly for type I or type II diabetes mellitus treatment. Additional possible indications are symptoms that are associated with diabetes mellitus. Preferably, a composition according to the present invention is used to control fasting, postprandial, and / or post-absorptive plasma glucose concentration, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss functional function of -cells of the pancreas, for the purpose of weight loss, and / or to prevent weight gain. [0067] The present invention further provides for the use of a composition according to the present invention in the manufacture of a medicament for treating diabetes mellitus, more particularly type I or type II, and / or the symptoms associated with it, as described herein. [0068] The present invention further provides a method for making a composition according to the present invention, comprising formulating a GLP-1 agonist and / or a pharmacologically tolerable salt thereof as methionine and, optionally, at least some pharmaceutically acceptable excipients . [0069] The present invention further provides for the use of a composition according to the present invention together with the administration of metformin, sulfonylurea, or glitazones, a long-acting insulin / insulin derivative, and / or a combination thereof, plus particularly as an add-on therapy in the administration of metformin. [0070] The present invention further provides for the use of a composition according to the present invention in patients whose blood sugar levels cannot be sufficiently controlled by the administration of metformin, sulfonylurea, or glitazones, a long-acting insulin / insulin derivative, and / or a combination thereof. [0071] The present invention further provides for the use of a composition according to the present invention in patients with type II diabetes as a supplement to a diet in order to improve blood sugar control. [0072] More particularly, a composition comprises desPro36 exendin-4 (1-39) -Lys6-NH2 (AVE0010), liraglutide and / or a pharmacologically tolerable salt together with methionine and / or a pharmacologically tolerable salt. [0073] More particularly, Lantus®, ΝεΒ29 -tetradecanoyl des (B30) human insulin, or Insuman® is useful as a long-acting insulin derivative. [0074] In particular, complementary therapy with metformin and / or a long-lasting insulin / insulin derivative and / or a pharmacologically tolerable salt thereof is preferred for the treatment of type II diabetes and / or obesity, more particularly in patients who are younger than 50 years and / or has a body mass index of at least 30, [0075] In the present invention, complementary therapy more particularly involves the treatment of type II diabetes with metformin and AVE0010. Metformin and AVE0010 can be administered within 24 hours. Metformin and AVE0010 can each be administered in a dosage once a day. Metformin and AVE0010 can be administered by means of different routes of administration. Metformin can be administered orally, and AVE0010 subcutaneously. [0076] Patients treated with complementary therapy according to the present invention can have an HbA1c value in the range of 7% to 10%. They are preferably in the age range of 18 to 50 years. [0077] The use in complementary therapy according to the present invention is more particularly applicable to patients in whom type II diabetes cannot be sufficiently controlled as metformin alone. [0078] More particularly, metformin is administered as follows: at least 1.0 g / day, preferably at least 1.5 g / day for 3 months. [0079] The invention is clarified by the following examples and figures. Subtitles [0080] Figures 1 and 2 show the content of the percentage of oxidized methionine Met (ox) with respect to the entire methionine content of AVE0010 after storage at different temperatures. 1: start of storage t0, 2: storage for 1 month. 3: storage for 3 months. 3: storage for 6 months. Figure 1: lot 894. Figure 2: lot 897. [0081] Figures 3 and 4 show the content of the percentage of impurities in the high molecular weight protein (with respect to AVE0010) after storage at different temperatures. 1: start of storage t0, 2: storage for 1 month. 3: storage for 3 months. 3: storage for 6 months. Figure 3: lot 894. Figure 4: lot 897. [0082] Figures 5 and 6 show the percentage content of all impurities (with respect to AVE0010) after storage at different temperatures. 1: start of storage tO, 2: storage for 1 month. 3: storage for 3 months. 3: storage for 6 months. Figure 5: lot 894. Figure 6: lot 897. Example 1 Liquid composition comprising AVE0010 and methionine [0083] The purpose of the study is the evolution of the chemical and / or physical stability of AVE0010 formulations (solution for injection, 0.1 mg / ml) with and without methionine, when the product is stored in cartridges under long-term conditions and accelerated conditions for up to 6 months. [0084] The following compositions are tested: [0085] The formulations are stored in the units that are intended for clinical studies and for sales and distribution. [0086] Storage time, storage conditions, moments are summarized in the following table: [0087] The formulations are stored horizontally. UR stands for relative humidity. Moment 0 is the start of storage. The measurements at time 0 are used as a reference for all conditions tested. During testing, samples are stored at +5 ± 3 ° C. [0088] • Descrição • Clareza da solução e cor das mesmas • pH • Estabilidade química (purezas e impurezas, determinadas por HPLC, mais particularmente a proporção de produtos de oxidação e de impurezas totais) • Proteínas de alto peso molecular, determinado por HPSEC • Partículas visíveis • Atividade biológica das formulações The physical and chemical stability of the stored formulations is determined with the help of the following tests: • Description • Clarity of solution and color • pH • Chemical stability (purities and impurities, determined by HPLC, more particularly the proportion of oxidation products and total impurities) • High molecular weight proteins, determined by HPSEC • Visible particles • Biological activity of formulations [0089] • Atividade biológica de AVE0010. Em 5°C e 25°C, atividade a-pós 6 meses foi pelo menos 96% da atividade inicial. As atividades das composições de acordo com a presente invenção foram maiores do que as atividades das composições comparativas. Em 40°C, atividade após 6 meses na ausência de metionina foi de aproximadamente 43%. Na presença de metionina, a atividade foi de aproximadamente 51% e assim claramente maior do que na ausência de metionina. • Produtos de oxidação. Medições foram executadas sobre um instrumento HPLC (modelo: aliança) a partir de Sistemas de Água, usando os 100% método da área de pico. Para a separação, uma gradiente de 0,1% TFA e acetonitrila como a fase móvel e uma coluna de fase reversa C18 (Júpiter) como a fase estacionária foi usadas. At 5°C, a proporção de metio-nina oxidada Met(ox) in AVE0010 na ausência de metionina foi 0,3%. Em 25°C, a proporção estava na faixa de 0,6-0,8%, em 40°C 1.3%. Quando a formulação da metionina composta, a proporção de metionina oxidada foi nitidamente inferior. Nunca foi mais do que 0,2% sob todas as condições testadas. Em 25°C, a proporção foi assim aproximadamente apenas 1/4 a 1/3 do conteúdo na ausência de metionina, até mesmo em 40°C aproximadamente apenas 1/6 (ver figuras 1 e 2). • Proteínas de alto peso molecular. Em 5°C, a proporção era de entre 0,1 e 0,3% e permaneceu substancialmente inalterada durante o tempo de armazenamento inteiro. Em 25°C, a proporção subiu na ausência de metionina a 0,9 e 1,3%, respectivamente. Na presença de metionina, a proporção foi 0,4 a 0,5% e assim pelo menos metade tão elevada. Em 40°C, a proporção foi na ausência de metionina 5,4% e 6,2%, respectivamente, enquanto era na presença de metionina apenas 1,6 e 1,7%, respectivamente, e assim claramente inferiores (ver figuras 3 e 4). • Impurezas totais. Em 5°C, impurezas totais subiram ao longo do tempo de armazenamento de 6 meses levemente a partir de 1,2 a 1,8 ou 1,9% (ausência de metionina). Quando metionina estava presente, a subida foi um pouco menor. Em 25°C, uma subida a 10,6% e 11,8%, respectivamente, observou-se. Na presença de metionina, os valores foram abaixo de 10%. Em 40°C, a proporção subiu até 54% (sem metionina). Quando a metionina estava presente, a proporção foi aproximadamente apenas 47% (ver figuras 5 e 6). The formulations were studied separately for the parallel lots (894 and 897) with reference to the following parameters: • Biological activity of AVE0010. At 5 ° C and 25 ° C, a-post 6-month activity was at least 96% of the initial activity. The activities of the compositions according to the present invention were greater than the activities of the comparative compositions. At 40 ° C, activity after 6 months in the absence of methionine was approximately 43%. In the presence of methionine, the activity was approximately 51% and thus clearly greater than in the absence of methionine. • Oxidation products. Measurements were performed on an HPLC instrument (model: alliance) from Water Systems, using the 100% peak area method. For the separation, a gradient of 0.1% TFA and acetonitrile as the mobile phase and a C18 reverse phase column (Jupiter) as the stationary phase were used. At 5 ° C, the proportion of oxidized methionine Met (ox) in AVE0010 in the absence of methionine was 0.3%. At 25 ° C, the proportion was in the range of 0.6-0.8%, at 40 ° C 1.3%. When the compound methionine formulation, the proportion of oxidized methionine was markedly lower. It was never more than 0.2% under all conditions tested. At 25 ° C, the proportion was thus only approximately 1/4 to 1/3 of the content in the absence of methionine, even at 40 ° C approximately only 1/6 (see figures 1 and 2). • High molecular weight proteins. At 5 ° C, the proportion was between 0.1 and 0.3% and remained substantially unchanged for the entire storage time. At 25 ° C, the proportion rose in the absence of methionine to 0.9 and 1.3%, respectively. In the presence of methionine, the proportion was 0.4 to 0.5% and so at least half as high. At 40 ° C, the proportion was in the absence of methionine 5.4% and 6.2%, respectively, while in the presence of methionine only 1.6 and 1.7%, respectively, and thus clearly lower (see figures 3 and 4). • Total impurities. At 5 ° C, total impurities rose over the 6-month storage period slightly from 1.2 to 1.8 or 1.9% (absence of methionine). When methionine was present, the rise was slightly less. At 25 ° C, a rise to 10.6% and 11.8%, respectively, was observed. In the presence of methionine, the values were below 10%. At 40 ° C, the proportion rose to 54% (without methionine). When methionine was present, the proportion was approximately only 47% (see figures 5 and 6). [0090] The percentage values are the content values (percentage of impurities) of oxidation products, total impurities, and high molecular weight proteins (HMWP). [0091] All values were determined by HPLC with the so-called 100% method. Here, in particular, it involves the reverse phase HPLC (C 18 column), in which a gradient method was used for the mobile phase: a) 0.1% TFA, 15% ACN and b) 0.1% TFA, 75% ACN. 215 nm (UV) detection. [0092] High molecular weight proteins (HMWP) were detected by FIPSEC, described in European Pharmacopoeia 6.0 for injectable insulin preparations. [0093] The data are summarized in the following table: [0094] • um agonista GLP-1 e/ou um sal farmacologicamente tolerável do mesmo (mais particularmente AVE0010 e/ou um sal farmacologicamente tolerável do mesmo), • opcionalmente pelo menos uma excipientes farmaceuticamente aceitáveis , • e metionina tem estabilidade melhorada e/ou integridade química. A proporção de metionina oxidada, de impurezas totais, e de proteínas de alto peso molecular é inferior nas composições de acordo com a presente invenção que nas composições comparativas. Uma composição de acordo com a presente invenção (lotes 894_B e 897_B) e as composições comparativas (lotes 894_A e 897 A) diferem na presença /ausência de metionina. Por esse motivo, a estabilidade melhorada e/ou a integridade química podem ser atribuídas ao componente de metionina nas composições de acordo com a presente invenção.The proportion of oxidation products, high molecular weight proteins, and total impurities is individually or together, a measure of the chemical integrity of the compositions. From the result described above with the example of the compositions, it follows that the liquid composition according to the present invention comprising • a GLP-1 agonist and / or a pharmacologically tolerable salt thereof (more particularly AVE0010 and / or a pharmacologically tolerable salt thereof), • optionally at least one pharmaceutically acceptable excipients, • and methionine has improved stability and / or chemical integrity. The proportion of oxidized methionine, total impurities, and high molecular weight proteins is lower in the compositions according to the present invention than in comparative compositions. A composition according to the present invention (lots 894_B and 897_B) and comparative compositions (lots 894_A and 897 A) differ in the presence / absence of methionine. For this reason, the improved stability and / or chemical integrity can be attributed to the methionine component in the compositions according to the present invention. [0095] In another experiment, it was studied as EDTA sodium and histidine has an effect on a composition according to the present invention. [0096] In a standard experimental design, rabbits were treated with composition B or C or a saline solution subcutaneously (s.c.) or intramuscularly (i.m.). In each case, half of the rabbits were sacrificed after 24 hours or 120 hours in order to determine the acute or sub-acute effects of administration histologically. Also, it was determined whether to repair / regenerate any changes that occurred. [0097] Then, subcutaneous injection of composition C, the animals shown after 24 hours, in contrast to the saline control, an illumination for moderate inflammatory reaction in the subcutaneous connective tissue. After subcutaneous injection 120 hours earlier, a clear trend was observed for the changes observed to repair by a fibroblastic reaction. Thus, compatibility could still be classified as moderate (instead of incompatible). [0098] With composition B, the animals shown after subcutaneous injection no or minimal differences for saline control (good compatibility). [0099] After the intramuscular injection of composition C, the animals exhibited muscle necrosis (multifocal or disseminated), clearly differing from the saline control, in which only the injection site was visible as a clearly circumscribed area of necrosis. With composition C, mineralization of necrotic muscle tissue was observed after 120 hours, visible even in an autopsy of the animals. Although small or focal mineralization at various locations in rabbits is not uncommon, mineralization after injection of composition C was clearly associated with the necrotic areas. Thus, the reversibility of the lesions caused by the injection is more than questionable. Based on these findings, composition C after intramuscular injection in rabbits was classified as incompatible. [0100] Composition B after intramuscular injection showed good compatibility (none or minimal differences for saline control). [0101] From these data, it follows that composition B, compared to composition C, had an improved compatibility in intramuscular or subcutaneous administration. Subcutaneous injection is the preferred route of administration for compositions comprising a GLP-1 agonist, more particularly AVE0010, described in this application. [0102] Thus, the compositions according to the present invention, which comprise a GLP-1 agonist, more particularly AVE0010, can be free of EDTA and / or histidine. Also, the compositions according to the present invention can be substantially free of EDTA and histidine.
权利要求:
Claims (9) [0001] Liquid composition, characterized by the fact that it comprises: a GLP-1 agonist in an amount of 0.01 to 1.5 mg / ml, or a pharmacologically tolerable salt of it, wherein the composition comprises methionine and is free of histidine, and wherein the GLP-1 agonist is desPro36 exendin-4 (1-39) -Lys6-NH2. [0002] Liquid composition according to claim 1, characterized in that it comprises one or more pharmaceutically acceptable excipients. [0003] Liquid composition according to claim 1 or 2, characterized in that it comprises a pharmaceutically acceptable preservative, more particularly m-cresol. [0004] Liquid composition according to any one of claims 1 to 3, characterized in that the composition comprises glycerol. [0005] Liquid composition according to any one of claims 1 to 4, characterized by the fact that the composition has a pH in the range from 3.5 to 5. [0006] Liquid composition according to any one of claims 1 to 5, characterized in that the composition comprises methionine in an amount ranging from 0.5 mg / ml to 20 mg / ml, preferably in an amount ranging from 1 mg / ml to 5 mg / ml. [0007] Liquid composition according to any one of claims 1 to 6, characterized in that the composition has the following constituents: (a) desPro36 exendin-4 (1-39) -Lys6-NH2, (b) sodium acetate, (c) m-cresol, (d) L-methionine, (e) 85% glycerol, (f) approximately 0.1 N hydrochloric acid, if a pH adjustment of approximately 4.5 is required, (g) approximately 0.1 N NaOH solution, if a pH adjustment of approximately 4.5 is required, and (h) water. [0008] Composition according to any one of claims 1 to 7, characterized in that it is an injectable composition. [0009] Use of a composition as defined in any one of claims 1 to 8, characterized in that it is for the manufacture of a medicament for the treatment of diabetes mellitus, more particularly type II diabetes.
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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2018-07-03| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]| 2018-12-26| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]| 2020-08-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2020-12-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 01/12/2020, OBSERVADAS AS CONDICOES LEGAIS. | 2021-05-25| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/11/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
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申请号 | 申请日 | 专利标题 DE102009052832|2009-11-13| DE102009052832.6|2009-11-13| DE102010011919.9|2010-03-18| DE102010011919A|DE102010011919A1|2010-03-18|2010-03-18|Liquid composition, useful for treating e.g. type II diabetes mellitus, and/or obesity, comprises a glucagon-like peptide-1 agonist and/or its salt e.g. exendin-4, optionally an adjuvant and methionine| PCT/EP2010/067249|WO2011058082A1|2009-11-13|2010-11-11|Pharmaceutical composition comprising a glp-1 agonist and methionine| 相关专利
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