Patent Application
20230061959
The invention relates to therapies for treating obesity, overweight and/or diabetes, in particular type 2 diabetes.
In recent times, obesity has spread rapidly in the world with the US and China being the most affected population. Today, 650 million of adults (13% of adults) and about 124 million of children older than 5 are obese in the world. In the US, 42.8% of adults and 18.5% of children are obese.
It has major health implications that can cause premature death due the increased risk of developing several diseases including type II diabetes, cerebrovascular disease, sleep apnea, cancers.
A weight loss of 10 to 15% is thought to significantly reduce the incidence of severe complications.
To treat this disease, therapies have focused on reducing food intake in patients.
Diet and physical activity are the foundations for treating obesity, but the use of medications is becoming a prevalent strategy for a long-term success over this disease.
Amylin receptor agonists are useful to reduce food intake and treating obesity.
Amylin receptor agonists and more particularly Pramlintide, a human amylin analog, have been identified to diminish the food intake but it slows down gastric emptying.
GLP-1 receptor agonist (GLP-1 RA), also known as incretin mimetics, are insulin secretagogues. Among GLP-1 RA can be cited exenatide and lixisenatide, which are also known for diminishing the food intake and for slowing down the gastric emptying.
Amylin receptor agonists, and more particularly pramlintide, and GLP-1 RA, such as exenatide and lixisenatide, have several side effects, for example nausea, which may cause a problem of tolerability.
Surprisingly, the applicant has demonstrated that a composition containing pramlintide in combination with exenatide allows reducing the slow-down of gastric emptying in comparison to an identical composition without exenatide. These compositions may thus exhibit a better tolerability profile and a better compliance of the patients.
The invention relates to a composition comprising at least one amylin receptor agonist, such as pramlintide, and at least one GLP-1 receptor agonist, such as exenatide or lixisenatide.
The invention also concerns a composition comprising pramlintide and a GLP-1 receptor agonist (GLP-1 RA) as only pharmaceutical active ingredients (API).
Pramlintide is an amylin receptor agonist and amylin analog which has been developed by the company Amylin to compensate the lack of physical stability of human amylin. This product, marketed under the name of Symlin®, was approved in 2005 by the FDA for the treatment of type 1 and type 2 diabetes, as a complement to insulin therapy.
Pramlintide is a peptide having the sequence:
Similarly to amylin, human GLP-1 cannot be used as a therapeutic treatment due to its extremely short half-life. Various GLP-1 derivatives, GLP-1 receptor agonists, referred to as GLP-1 RA, or GLP-1 analogs reproduce the effects of GLP-1, while having a longer half-life. One such FDA drug is Byetta® (exenatide) which is a synthetic product of exendin-4.
GLP-1 is also described to play a similar role to that of amylin as a meal-induced inhibitory signal.
In an embodiment, the GLP-1, GLP-1 analogs, or GLP-1 RA are “short-acting” or “prandial.” “Short-acting” or “prandial” is understood to mean GLP-1, GLP-1 analogs, or GLP-1 RA of which the apparent half-life of elimination after subcutaneous injection in humans is less than 8 hours, in particular less than 5 hours, preferably less than 4 hours or else less than 3 hours, such as, for example, exenatide or lixisenatide.
In an embodiment, the GLP-1, the GLP-1 analogs, or the GLP-1 RA are selected from the group consisting of exenatide (Byetta®, ASTRA-ZENECA), lixisenatide (Lyxumia®, SANOFI), the analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
Exenatide is a peptide having the sequence:
Lixisenatide is a peptide having the sequence:
Exenatide and lixisenatide, are described in the applications US2004/0023871 and WO0104156, entirely included herein by reference.
In an embodiment, the GLP-1, the GLP-1 analog, or GLP-1 RA is exenatide or Byetta®, analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In an embodiment, the GLP-1, the GLP-1 analog, or GLP-1 RA is lixisenatide or Lyxumia®, analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
In an embodiment the invention concerns, a composition comprising pharmaceutical active ingredients (API) chosen in the group consisting of pramlintide and a GLP-1 receptor agonist (GLP-1 RA).
In an embodiment the invention relates to a composition, characterized in that it comprises only amylin RA and GLP-1 RA as API.
In an embodiment the invention relates to a composition, characterized in that it comprises only pramlintide and exenatide as API.
In an embodiment the invention relates to a composition, characterized in that it comprises only pramlintide and lixisenatide as API.
In an embodiment the invention concerns a composition characterized in that the GLP-1 receptor agonist (GLP-1 RA) is chosen amongst lixisenatide and exenatide.
In one embodiment the GLP-1 receptor agonist (GLP-1 RA) is lisixenatide.
In one embodiment the GLP-1 receptor agonist (GLP-1 RA) is exenatide.
The invention also relates to a composition comprising pharmaceutical active ingredients (API) chosen in the group consisting of pramlintide and exenatide.
The invention also relates to a composition comprising pharmaceutical active ingredients (API) chosen in the group consisting of pramlintide and lixisenatide.
The invention also relates to stable pharmaceutical formulation including said composition.
In an embodiment the invention relates to a composition in the form of an aqueous solution.
In an embodiment the invention relates to a composition in the form of an injectable aqueous solution.
In an embodiment the invention relates to a composition in the form of an injectable aqueous formulation.
Such formulation is typically a solution or a suspension.
In a further embodiment of the invention the pharmaceutical formulation is an aqueous solution.
The term “aqueous formulation” is defined as a formulation comprising at least 50% w/w water.
Likewise, the term “aqueous solution” is defined as a solution comprising at least 50% w/w water, and the term “aqueous suspension” is defined as a suspension comprising at least 50% w/w water.
The compositions in the form of an injectable aqueous solution according to the invention are clear solutions. “Clear solution” is understood to mean compositions which satisfy the criteria described in the American and European pharmacopoeias concerning the injectable solutions. In the US pharmacopoeia, the solutions are defined in part <1151> referring to the injection (<1>) (referring to <788> according to USP 35 and specified in <788> according to USP 35 and in <787>, <788> and <790> USP 38 (from Aug. 1, 2014), according to USP 38). In the European pharmacopoeia, the injectable solutions have to meet the criteria given in sections 2.9.19 and 2.9.20.
In an embodiment the invention relates to a composition, in the form of a solution comprising an aprotic polar solvent.
In an embodiment the solution comprises at least 60% of an aprotic polar solvent.
In an embodiment the solution comprises at least 75% of an aprotic polar solvent.
In an embodiment the solution comprises less than 25% of water.
In an embodiment the solution comprises less than 20% of water.
In an embodiment the solution comprises less than 15% of water.
In an embodiment the solution comprises less than 10% of water.
In an embodiment the solution comprises less than 5% of water.
In an embodiment the solution comprises an aprotic polar solvent chosen from a group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, n-methyl pyrrolidone (NMP), dimethylacetamide (DMA), and propylene carbonate.
In an embodiment, the solution comprises dimethyl sulfoxide (DMSO).
In an embodiment, the solution comprises as solvent dimethyl sulfoxide (DMSO) and less than 25% of water.
In an embodiment the invention relates to a composition in solid form.
In an embodiment the invention relates to a composition in powder form.
In an embodiment the invention relates to a dried-form composition.
In an embodiment the invention relates to a spray-dried composition.
In an embodiment the invention relates to a freeze-dried composition
In one embodiment the physician or the patient adds solvents and/or diluents prior to use.
In another embodiment the pharmaceutical formulation is a dried form formulation (e.g. freeze-dried or spray-dried) ready for use without any prior dissolution.
By “dried form” is intended the liquid pharmaceutical composition or formulation is dried either by freeze-drying (i.e., lyophilization), spray-drying or air-drying.
If the composition is a solution the contents of the different constituents are given in in weight per volume.
If the composition is a solid composition the contents of the different constituents are given in weight per weight.
In an embodiment the invention relates to a composition, wherein the pH is ranging from 3.5 to 4.4.
In an embodiment the invention relates to a composition, wherein the pH of the solution is comprised from 3.5 to 4.4.
In an embodiment the invention relates to a composition, wherein the pH of the solution is comprised from 3.7 to 4.2.
In an embodiment the invention relates to a composition, wherein the pH of the solution is about 4.0.
In an embodiment the invention relates to a composition, wherein the pH of the solution is ranging from 6.8 to 7.4.
The invention also relates to a composition according to the invention which is intended to be used in an obesity treatment method, characterized in that it enables to decrease the food consumption. Obese person being defined as person having a BMI (body mass index) of 30 or higher.
The invention also relates to a composition according to the invention which is intended to be used in an overweight treatment method, characterized in that it enables to decrease the food consumption. Overweight person being defined as person having a BMI from 25 to less than 30.
In an embodiment the composition according to the invention is intended to be used in an overweight or obesity treatment method for person having a BMI of 25 or higher.
In an embodiment the composition according to the invention is intended to be used in an overweight or obesity treatment method for person having a BMI of 27 or higher.
The invention also relates to a composition according to the invention which is intended to be used in method for the treatment of diabetes, characterized in that it enables to decrease the food consumption.
The invention also relates to a composition according to the invention which is intended to be used in an obesity treatment method, characterized in that it improves loss of weight or limit the gain of weight.
In an embodiment, the compositions according to the invention lead to a slow-down of the gastric emptying of at least 5% inferior to an identical composition without the corresponding GLP-1 RA.
In one embodiment, the composition comprises pramlintide at a concentration ranging from 0.3 to 10 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from 0.5 to 10 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from 0.6 to 6 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from 0.9 to 4 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from to 4 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from to 3 mg/ml.
In one embodiment, the composition comprises pramlintide at a concentration ranging from to 2 mg/ml.
In one embodiment, the pramlintide concentration is 0.6 mg/ml.
In one embodiment, the pramlintide concentration is 1 mg/ml.
In one embodiment, the pramlintide concentration is 1.5 mg/ml.
In one embodiment, the pramlintide concentration is 2 mg/ml.
In one embodiment, the pramlintide concentration is 2.5 mg/ml.
In one embodiment, the pramlintide concentration is 3 mg/ml.
In one embodiment, the pramlintide concentration is 3.5 mg/ml.
In one embodiment, the pramlintide concentration is 4 mg/ml.
In one embodiment, the pramlintide concentration is 4.5 mg/ml.
In one embodiment, the pramlintide concentration is 5 mg/ml.
In one embodiment, the composition comprises pramlintide in an amount less than or equal to 20% w/w.
In one embodiment, the composition comprises pramlintide in an amount less than or equal to 15% w/w.
In one embodiment, the composition comprises pramlintide in an amount less than or equal to 10% w/w.
In one embodiment, the composition comprises pramlintide in an amount less than or equal to 5% w/w.
In one embodiment, the composition comprises pramlintide in an amount comprised from 1 to 20% w/w.
In one embodiment, the composition comprises pramlintide in an amount comprised from 2 to 15% w/w.
In one embodiment, the composition comprises exenatide at a concentration ranging from to 500 μg/ml.
In one embodiment, the composition comprises exenatide at a concentration ranging from to 200 μg/ml
In one embodiment, the composition comprises exenatide at a concentration ranging from to 400 μg/ml.
In one embodiment, the composition comprises exenatide at a concentration ranging from to 300 μg/ml.
In one embodiment, the composition comprises exenatide at a concentration ranging from to 250 μg/ml.
In one embodiment, the composition comprises exenatide at a concentration ranging from 100 to 200 μg/ml.
In one embodiment the exenatide concentration is 50 μg/ml.
In one embodiment the exenatide concentration is 75 μg/ml.
In one embodiment the exenatide concentration is 100 μg/ml.
In one embodiment the exenatide concentration is 125 μg/ml.
In one embodiment the exenatide concentration is 150 μg/ml.
In one embodiment the exenatide concentration is 175 μg/ml.
In one embodiment the exenatide concentration is 200 μg/ml.
In one embodiment the exenatide concentration is 250 μg/ml.
In one embodiment the exenatide concentration is 300 μg/ml.
In one embodiment the exenatide concentration is 350 μg/ml.
In one embodiment the exenatide concentration is 400 μg/ml.
In one embodiment the exenatide concentration is 450 μg/ml.
In one embodiment the exenatide concentration is 500 μg/ml.
In one embodiment, the composition comprises exenatide in an amount less than or equal to 10% w/w.
In one embodiment, the composition comprises exenatide in an amount less than or equal to 7.5% w/w.
In one embodiment, the composition comprises exenatide in an amount less than or equal to 5% w/w.
In one embodiment, the composition comprises exenatide in an amount less than or equal to 2.5% w/w.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from to 12504 ml.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from 125 to 1000 μg/ml.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from 150 to 1000 μg/ml.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from 200 to 750 μg/ml.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from 225 to 650 μg/ml.
In one embodiment, the composition comprises lixisenatide at a concentration ranging from 250 to 500 μg/ml.
In one embodiment the lixisenatide concentration is 150 μg/ml.
In one embodiment the lixisenatide concentration is 200 μg/ml.
In one embodiment the lixisenatide concentration is 250 μg/ml.
In one embodiment the lixisenatide concentration is 300 μg/ml.
In one embodiment the lixisenatide concentration is 350 μg/ml.
In one embodiment the lixisenatide concentration is 400 μg/ml.
In one embodiment the lixisenatide concentration is 450 μg/ml.
In one embodiment the lixisenatide concentration is 500 μg/ml.
In one embodiment the lixisenatide concentration is 550 μg/ml.
In one embodiment the lixisenatide concentration is 600 μg/ml.
In one embodiment the lixisenatide concentration is 650 μg/ml.
In one embodiment the lixisenatide concentration is 700 μg/ml.
In one embodiment the lixisenatide concentration is 750 μg/ml.
In one embodiment the lixisenatide concentration is 800 μg/ml.
In one embodiment, the composition comprises lixisenatide in an amount less than or equal to 30% w/w.
In one embodiment, the composition comprises lixisenatide in an amount less than or equal to 20% w/w.
In one embodiment, the composition comprises lixisenatide in an amount less than or equal to 15% w/w.
In one embodiment, the composition comprises lixisenatide in an amount less than or equal to 7.5% w/w.
In one embodiment, the composition is characterized in that ratio pramlintide/exenatide (weight/weight) is ranging from 2 to 50.
In one embodiment, the composition is characterized in that ratio pramlintide/exenatide (weight/weight) is ranging from 2 to 30.
In one embodiment, the composition is characterized in that ratio pramlintide/exenatide (weight/weight) is ranging from 3 to 25.
In one embodiment, the composition is characterized in that ratio pramlintide/exenatide (weight/weight) is ranging from 5 to 20.
In one embodiment, the composition is characterized in that ratio pramlintide/exenatide (weight/weight) is ranging from 8 to 15.
In one embodiment, the composition is characterized in that it comprises from 20 to 400 μg of Exenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 30 to 200 μg of Exenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 40 to 150 μg of Exenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 40 to 120 μg of Exenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that ratio pramlintide/lixisenatide (weight/weight) is ranging from 0.7 to 20.
In one embodiment, the composition is characterized in that ratio pramlintide/lixisenatide (weight/weight) is ranging from 0.7 to 15.
In one embodiment, the composition is characterized in that ratio pramlintide/lixisenatide (weight/weight) is ranging from 1.2 to 8.
In one embodiment, the composition is characterized in that ratio pramlintide/lixisenatide (weight/weight) is ranging from 1.8 to 7.
In one embodiment, the composition is characterized in that ratio pramlintide/lixisenatide (weight/weight) is ranging from 2.5 to 6.
In one embodiment, the composition is characterized in that it comprises from 50 to 1000 μg of lixisenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 75 to 500 μg of lixisenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 100 to 375 μg of lixisenatide per mg of Pramlintide.
In one embodiment, the composition is characterized in that it comprises from 100 to 300 μg of lixisenatide per mg of Pramlintide.
In an embodiment, the composition according to the invention moreover includes buffers.
In an embodiment, the composition according to the invention includes a buffer selected from the group consisting of a sodium acetate buffer and Tris buffer.
In one embodiment, the composition is characterized in that it comprises a sodium acetate buffer.
In one embodiment, the composition is characterized in that it comprises a Tris buffer
In an embodiment, the composition according to the invention moreover includes preservatives.
In an embodiment, the preservatives are selected from the group consisting of m-cresol and phenol, alone or in a mixture.
In an embodiment, the concentration of preservatives is from 10 to 50 mM.
In an embodiment, the concentration of preservatives is from 10 to 40 mM.
In an embodiment, the composition according to the invention moreover includes a surfactant.
In an embodiment, the surfactant is selected from the group consisting of Poloxamer 188, Tween® 20, also referred to as Polysorbate 20, and Tween® 80, also referred to as Polysorbate 80.
In an embodiment, the Tween® 20 concentration varies from 5 to 50 μg/mL.
In an embodiment, the Tween® 20 concentration varies from 5 to 25 μg/mL.
In an embodiment, the Tween® 20 concentration is 10 μg/mL
In one embodiment, the composition is characterized in that the concentration of Poloxamer 188 is ranging from 5 to 50 μg/ml.
In one embodiment, the composition is characterized in that the concentration of Poloxamer 188 is ranging from 5 to 25 μg/ml.
In one embodiment, the composition is characterized in that the concentration of Poloxamer 188 is 10 μg/mL.
In an embodiment the composition further comprises an absorption enhancer.
In an embodiment, the absorption enhancer is chosen from the group consisting of SNAC, N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), 8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC), 8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB) and sodium salts thereof.
In an embodiment the absorption enhancer is SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).
In one embodiment, the composition comprises an absorption enhancer in an amount comprised from 50 to 90% w/w.
In one embodiment, the composition comprises an absorption enhancer in an amount comprised from 55 to 85% w/w.
In one embodiment, the composition comprises an absorption enhancer in an amount comprised from 70 to 80% w/w.
In one embodiment, the composition comprises an absorption enhancer in an amount at least 5% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 10% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 15% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 20% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 25% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 30% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 35% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 40% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 45% w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 50% w/w.
In one embodiment, the composition comprises an absorption enhancer in an amount at least 55 w/w
In one embodiment, the composition comprises an absorption enhancer in an amount at least 60% w/w
The composition according to the invention can moreover include additives such as tonicity agents.
In an embodiment, the tonicity agents are selected from the group consisting of glycerol, sodium chloride, mannitol and glycine.
In an embodiment, the composition according to the invention further includes an antioxidant.
In an embodiment, the antioxidant is methionine.
In an embodiment, the composition according to the invention is characterized in that it does not comprise insulin.
In an embodiment, the composition according to the invention is characterized in that it does not comprise human insulin.
In an embodiment, the composition according to the invention is characterized in that it does not comprise insulin chosen amongst human insulin analogs.
In an embodiment, the composition according to the invention is characterized in that it does not comprise human insulin analogs chosen amongst insulin aspart (NovoLog® from NOVO NORDISK), insulin lispro (Humalog® from ELI LILLY) and glulisine insulin (Apidra® from SANOFI).
In an embodiment, the composition according to the invention is characterized in that it does not comprise human insulin analogs chosen amongst insulin comprising at least the A21G mutation.
In an embodiment, the composition according to the invention is characterized in that it does not comprise human insulin analogs chosen amongst insulin analogs A21G, B28D, desB30 and A21G, B28E, desB30 described in application WO2007104786 entirely included herein by reference.
In an embodiment, the composition according to the invention does not comprise the human insulin analog comprising only the mutation A21G.
This human insulin analog comprising only the mutation A21G has the following sequences:
In an embodiment, the composition according to the invention is characterized in that it does not comprise insulin glargine.
In an embodiment, the composition according to the invention is characterized in that it does not comprise glucagon or glucagon analogs.
In an embodiment, the composition according to the invention does not comprise co-polyaminoacids bearing carboxylate charges and hydrophobic radicals.
In an embodiment, the hydrophobic radicals are chosen amongst those as described in the application US2019274954A1 entirely included herein by reference.
In an embodiment said hydrophobic radicals are chosen amongst the radicals according to formula X as defined below:
wherein
In an embodiment, the composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges and hydrophobic radicals as described in the application US20190328842A1 entirely included herein by reference.
In an embodiment the composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted of glutamic or aspartic units and said hydrophobic radicals -Hy chosen among the radicals according to formula X1 as defined below:
In which
In an embodiment composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges and hydrophobic radicals as described in the application US2019274954A1 entirely included herein by reference.
In an embodiment composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges carboxylates and at least one hydrophobic radical -Hy according to formula X as defined above, said co-polyamino acid being chosen among the co-polyamino acids according to formula I2:
[Q(PLG)k2][Hy]j2[Hy]j′2 Formula I2
In an embodiment composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges and hydrophobic radicals as described in the applications US20180193421A1 and US2019275108A1 entirely included herein by reference.
In an embodiment composition according to the invention is characterized in that it does not comprise a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid consisting of glutamic or aspartic units and said hydrophobic radicals Hy having the following formula I3:
in which
In an embodiment composition according to the invention is characterized in that it does not comprise an amphiphilic compound comprising a hydrophilic backbone substituted by hydrophobic radicals as described in the application PCT/EP/2019/070953 entirely included herein by reference.
In an embodiment composition according to the invention is characterized in that it does not comprise an amphiphilic compound comprising a hydrophilic backbone substituted hydrophobic radicals Hy, said hydrophobic radicals being chosen from formula I4:
the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic backbone HB or the above radicals (I4, II4, II′4, II″4, III4 and IV4) to each other by amide functions;
The invention also concerns a composition for use in the method for the treatment of obesity.
The invention also concerns a composition for use in the method for the treatment of overweight.
The invention also concerns a composition for use in the method for the treatment of diabetes, in particular type 2 diabetes.
In an embodiment the method of treatment concerns animals.
In another embodiment the method of treatment concerns mammals.
In another embodiment the method of treatment concerns mammals pets, such as dogs and cats.
In another embodiment the method of treatment concerns human beings.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect of gastric emptying of amylin RA as compared to the same composition without GLP-1 RA.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect on gastric emptying of amylin RA as compared to the same composition without GLP-1 RA by at least 5%.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect on gastric emptying of amylin RA as compared to the same composition without GLP-1 RA by at least 10%.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect on gastric emptying of amylin RA as compared to the same composition without GLP-1 RA by at least 20%.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect on gastric emptying of amylin RA as compared to the same composition without GLP-1 RA by at least 30%.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces the slowing effect on gastric emptying of amylin RA as compared to the same composition without GLP-1 RA by at least 40%.
In one embodiment, the composition according to the invention is for use in the method for the treatment of obesity, overweight and/or diabetes, in particular type 2 diabetes, characterized in that it reduces at least one adverse effect as compared to the same composition without GLP-1 RA.
In one embodiment, the composition according to the invention for the treatment of obesity, overweight and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 150 to 2000 μg/day.
In one embodiment, the composition according to the invention for the treatment of obesity and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 250 to 1800 μg/day.
In one embodiment, the composition according to the invention for the treatment of obesity and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 300 to 1500 μg/day.
In one embodiment, the composition according to the invention for the treatment of obesity and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 350 to 1200 μg/day.
In one embodiment, the composition according to the invention for the treatment of obesity and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 400 to 1000 μg/day.
In one embodiment, the composition according to the invention for the treatment of obesity and/or diabetes, in particular Type 2 Diabetes, is characterized in that the daily dose of pramlintide is ranging from 400 to 800 μg/day.
Compositions according to any of the preceding claims, characterized in that the daily dose of exenatide is ranging from 10 to 250 μg.
In one embodiment, the composition according to the invention, is characterized in that the daily dose of exenatide is ranging from 20 to 200 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of exenatide is ranging from 25 to 180 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of exenatide is ranging from 30 to 160 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of exenatide is ranging from 35 to 140 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of exenatide is ranging from 40 to 120 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of lixisenatide is ranging from 25 to 600 μg.
In one embodiment, the composition according to the invention, is characterized in that the daily dose of lixisenatide is ranging from 50 to 500 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of lisxenatide is ranging from 65 to 450 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of lisxenatide is ranging from 75 to 400 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of lixisenatide is ranging from 85 to 350 μg.
Compositions according to any of the preceding claims, characterized in that the daily dose of lixisenatide is ranging from 95 to 300 μg.
The invention also concerns a container comprising a pharmaceutical formulation according to the invention.
In one embodiment the container is a cartridge.
In one embodiment the container is a vial.
The invention also concerns an injection or delivery device comprising a pharmaceutical formulation according to the invention.
In one embodiment, the injection or delivery device comprises a pharmaceutical formulation according to the invention.
In one embodiment, the injection or delivery device is a pump.
In one embodiment, the injection or delivery device delivers the pharmaceutical formulation continuously.
In one embodiment, the injection or delivery device delivers microboluses of the pharmaceutical formulation.
In one embodiment, the injection or delivery device is a patch pump
In one embodiment, the injection or delivery device is an osmotic pump.
Composition according to the invention comprises 0.6 mg/mL of pramlintide and 24 μg/mL of exenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 36 μg/mL of exenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 48 μg/mL of exenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 60 μg/mL of exenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 72 μg/mL of exenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 40 μg/mL of exenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 60 μg/mL of exenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 80 μg/mL of exenatide
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 100 μg/mL of exenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 120 μg/mL of exenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 80 μg/mL of exenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 120 μg/mL of exenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 160 μg/mL of exenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 200 μg/mL of exenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 240 μg/mL of exenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 120 μg/mL of exenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 180 μg/mL of exenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 240 μg/mL of exenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 300 μg/mL of exenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 360 μg/mL of exenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 160 μg/mL of exenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 240 μg/mL of exenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 320 μg/mL of exenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 400 μg/mL of exenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 460 μg/mL of exenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 24 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 36 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 48 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 60 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 72 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 40 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 60 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 80 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 100 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 120 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 80 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 120 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 160 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 200 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 240 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 120 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 180 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 240 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 300 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 360 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 160 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 240 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 320 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 400 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 460 μg/mL of exenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 60 μg/mL of lixisenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 90 μg/mL of lixisenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 120 μg/mL of lixisenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 150 μg/mL of lixisenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide and 180 μg/mL of lixisenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 100 μg/mL of lixisenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 150 μg/mL of lixisenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 200 μg/mL of lixisenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 250 μg/mL of lixisenatide.
Composition according to the invention, comprises 1.00 mg/mL of pramlintide and 300 μg/mL of lixisenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 200 μg/mL of lixisenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 300 μg/mL of lixisenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 400 μg/mL of lixisenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 500 μg/mL of lixisenatide.
Composition according to the invention, comprises 2.00 mg/mL of pramlintide and 600 μg/mL of lixisenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 300 μg/mL of lixisenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 450 μg/mL of lixisenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 600 μg/mL of lixisenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 750 μg/mL of lixisenatide.
Composition according to the invention, comprises 3.00 mg/mL of pramlintide and 900 μg/mL of lixisenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 400 μg/mL of lixisenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 600 μg/mL of lixisenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 800 μg/mL of lixisenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 1000 μg/mL of lixisenatide.
Composition according to the invention, comprises 4.00 mg/mL of pramlintide and 1200 μg/mL of lixisenatide.
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 60 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 90 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 120 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 150 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 0.6 mg/mL of pramlintide, 180 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 100 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 150 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 200 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 250 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 1.00 mg/mL of pramlintide, 300 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 200 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 300 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 400 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 500 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 2.00 mg/mL of pramlintide, 600 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 300 of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 450 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 600 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 750 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 3.00 mg/mL of pramlintide, 900 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 400 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 600 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 800 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 1000 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
Composition according to the invention, comprises 4.00 mg/mL of pramlintide, 1200 μg/mL of lixisenatide and m-cresol (20 mM), Acetate buffer (20 mM), Mannitol (250 mM).
The compositions according to the invention can moreover include excipients in compliance with the Pharmacopoeias, in particular the EP and/or US Pharmacopoeias.
According to an embodiment, the composition can be in solid or lyophilized form. This composition can then be used to reconstitute a solution or a formulation.
The methods of administration considered are the intravenous, subcutaneous, intradermal or intramuscular route.
According to an embodiment, the method of administration is the subcutaneous route.
The transdermal, oral, nasal, vaginal, ocular, buccal, pulmonary administration routes are also considered.
The invention also relates to single-dose formulations.
In an embodiment, the formulations are in the form of an injectable solution.
The preparation of a composition according to the invention has the advantage that it can be implemented by simple mixing of an aqueous solution of pramlintide and of exenatide or lixisenatide, in aqueous solution or in lyophilized form.
If necessary, the composition of the mixture is adjusted in terms of excipients such as glycerol, m-cresol and polysorbate 20 (Tween® 20). This addition can be carried out by addition of concentrated solutions of said excipients.
This solution is a commercial solution of exenatide marketed by the company NOVO NORDISK under the name of Byetta®. The excipients in this composition C1 are detailed in Table 1.
Exenatide powder (obtained by peptide synthesis) is dissolved with a 10 mM HCl solution. An acetate buffer solution is then added to give the composition C1′. The composition is detailed in Table 1.
A 5 mg/mL concentrated solution of pramlintide (obtained by peptide synthesis) and excipients is prepared via a stepwise addition in an empty container in the following order: m-cresol, acetate buffer, mannitol and pramlintide. Sufficient quantity of water is then added and the pH is adjusted to 4 to obtain composition C2 which is detailed in Table 1.
Pramlintide powder (obtained by peptide synthesis) is dissolved with a 10 mM HCl solution. An acetate buffer solution is then added to give the composition C2′. The composition is detailed in Table 1.
Lixisenatide powder (obtained by peptide synthesis) is dissolved with a 10 mM HCl solution. An acetate buffer solution is then added to give the composition C3. The composition is detailed in Table 1.
A concentrated solution of excipients is prepared via a stepwise addition in an empty container in the following order: m-cresol, acetate buffer and mannitol. Sufficient quantity of water is then added and the pH is adjusted to 4 to obtain Composition C4. This composition is detailed in Table 1.
A concentrated solution of excipients is prepared via a stepwise addition in an empty container in the following order: BSA (Bovine Serum Albumine), acetate buffer, NaCl and polysorbate 20. Sufficient quantity of water is then added and the pH is adjusted to 4 to obtain Composition C5.
To a volume VC4 of the composition C4, as prepared in example C4, is added a VC5 of the dilution solution C5, as prepared in example C5 to obtain the final solution C6 which composition is detailed in Table 1.
The dilution solution (Composition C5) is used to dilute the solution of pramlintide (Composition C2) and of exenatide (Composition C1—Byetta) to prepare the solutions C7-1 to C7-8 as shown in Table 1 that will be injected to the animals during the in vivo assays.
The compositions of pramlintide and exenatide C7-9 to C7-33 are obtained by mixing a VC4 of composition C4, a volume VC1′ or VC1 of the composition of exenatide C1′ or C1 and a VC2′ of the composition of pramlintide C2′.
The compositions of pramlintide and lixisenatide C8-1 to C8-24 are obtained by mixing a VC4 of composition C4, a volume VC3 of the composition of lixisenatide C3 and a VC2′ of the composition of pramlintide C2′.
Effects of Pramlintide and Pramlintide with Exenatide Compositions on Gastric Emptying
The aim of this study was to evaluate the effects of pramlintide compositions C7-1 and C7-2 and pramlintide combined with exenatide compositions (C7-3 to C7-5) on gastro-intestinal transit (gastric emptying) in the mouse.
Studies were conducted on naïve male Swiss mice (Janvier Lab) as no gender specific effect were expected. Body weight range of 25-32 g were included in the analysis.
Mice were approximately fasted for 18 hours (˜T0−18 h). The gastric emptying (i.e. stomach content) was measured via the administration of a suspension of charcoal at T0 (activated charcoal (0.4 ml/mouse, ˜0.4 mg/mouse; Sigma Reference number C9157), suspended 10% with 2.5% arabic gum in distilled water). The studied composition or a vehicle (as a standard control) was administered subcutaneously using Hamilton syringes 20 minutes before charcoal (T0−20 min), then 50 minutes later (T0+50 min), they were sacrificed, and the stomach was removed. The stomach was excised from the abdomen and weighed with its contents (full stomach weight). Afterwards, the stomach was opened, the contents washed out and the weight recorded again (empty stomach weight).
The results are expressed as the variation of gastric content with the administration compositions comprising pramlintide compared with the gastric content with administration the vehicle (weight of gastric content with pramlintide/weight of gastric content with vehicle).
Measurements of the gastric emptying for compositions C7-2 were obtained according to the general procedure. Five different doses of pramlintide were studied. Each dose was tested on 4 mice. The results of this study are presented in table 2.
These examples demonstrate that subcutaneous injection of a composition comprising pramlintide alone increases the stomach content weight i.e. slows down the gastric emptying.
Measurements of the gastric emptying for compositions C6 and C7-1 to C7-5 were obtained according to the general procedure described in example D1. Two sets of experiments were carried out. Each dose was tested on 8 mice apart for composition C7-2 that was tested on 10 mice. The results are presented in table 3.
These results show that pramlintide alone increases the gastric content weight i.e. slows down the gastric emptying and that the addition of exenatide to pramlintide decreases the gastric content weight in comparison with the same composition without exenatide i.e. increase the gastric emptying.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20154980.5 | Jan 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/052342 | 2/1/2021 | WO |
