WO2022243528A1 - Utilisation d'une composition comprenant de l'orlistat et de l'acarbose pour obtenir une perte de poids prolongée - Google Patents

Utilisation d'une composition comprenant de l'orlistat et de l'acarbose pour obtenir une perte de poids prolongée Download PDF

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WO2022243528A1
WO2022243528A1 PCT/EP2022/063758 EP2022063758W WO2022243528A1 WO 2022243528 A1 WO2022243528 A1 WO 2022243528A1 EP 2022063758 W EP2022063758 W EP 2022063758W WO 2022243528 A1 WO2022243528 A1 WO 2022243528A1
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orlistat
acarbose
use according
composition
weight
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PCT/EP2022/063758
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English (en)
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Jan Stefan Persson GRUDÉN
Anders Forslund
Ulf HOLMBÄCK
Jan Arvid SÖDERHALL
Göran ALDERBORN
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Empros Pharma Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to body weight management and how to obtain a sustainable body weight loss.
  • Elements in body weight management are i) treatment with a weight-lowering drug substance and ii) treatment with a combination of orlistat and acarbose to reduce fluctuation in body weight so that the body weight stays within a range of ⁇ 6% within a 6-month period such as ⁇ 3% within a 3-month period from the body weight resulting after the treatment with said weightlowering drug substance.
  • the worldwide prevalence is estimated to be 1.5 billion overweight and 500 million obese individuals. Overall, more than one out of ten of the world's adult population is obese. In 2010, more than 40 million children under five were overweight. Once considered a high-income country problem, overweight and obesity are now on the rise in low- and middle-income countries, particularly in urban settings. Overweight and obesity are the fifth leading risks for global deaths. At least 2.8 million adults die each year globally as a result of being overweight or obese. In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden and between 7% and 41% of certain cancer burdens are attributable to overweight and obesity. In June 2013, the American Medical Association officially recognized obesity as a disease.
  • Type 2-diabetes is growing epidemically, and this rise is closely associated with obesity.
  • Type 2- diabetes has multiple manifestations and sub-optimal treatment is associated with progressive beta-cell failure.
  • lifestyle measures including eating habits and physical activity, should be first-line treatment, success is difficult to achieve, and pharmaceutical intervention is almost always required.
  • the patients Before manifest type 2-diabetes is diagnosed, the patients usually have a period of impaired glucose tolerance. If this impaired glucose tolerance, which may precede or follow weight gain, is correctly treated, the progression towards diabetes might be halted or averted. Current treatment options are limited to lifestyle changes, or secondly metformin. Hence, there is a need for a novel safe and efficient medical treatment.
  • PCOS Polycystic Ovary Syndrome
  • PCOS Polycystic ovary syndrome
  • One of the most common immediate symptoms is insulin resistance. This insulin resistance is often associated with obesity, type 2 diabetes, and high cholesterol levels.
  • Current recommended pharmacological treatment (in addition to contraceptives) of the obese and/or glucose impaired PCOS patients is limited to metformin, although current guidelines state that the evidence base is not strong.
  • Other insulin sensitizers for example thiazolidinediones, have unwanted risk/benefit ratio and are not recommended.
  • PCOS patients there is a clinical need for a drug that safely both decreases weight and improves glucose tolerance.
  • Nonalcoholic steatohepatitis is liver inflammation and damage caused by a buildup of fat in the liver. NASH affects 2 to 5 percent of Americans. An additional 10 to 20 percent of Americans have fat in their liver, but no inflammation or liver damage, a condition called “fatty liver.” or NAFLD. Both NASH and NAFLD are becoming more common, possibly because of the greater number of Americans with obesity. Currently, no specific therapies for NASH exist, except for lifestyle interventions, so there exists an unmet clinical need.
  • HDL high-density lipoprotein
  • the present inventors postulate that the proposed product will directly or indirectly affect most of the components of the metabolic syndrome, mainly decreasing weight, improving glucose control, which in turn will lead to improved hepatic fat metabolism with decreased triglycerides concentration.
  • the product is expected to also have direct effect on triglyceride concentration.
  • Lorcaserin is a selective serotonin 2C (5HT2c) receptor agonist that was anticipated to recapitulate the weight loss effects of fenfluramine without its adverse cardiac effects. Lorcaserin decreased body weight modestly, by about 3.2 kg (-3.2% of initial body weight) more than placebo- Among patients with diabetes, lorcaserin treatment led to lower body weight and improved glycated hemoglobin concentrations.
  • 5HT2c serotonin 2C
  • Liraglutide (Saxenda®; liraglutide injection) was approved (both by EMA and FDA) as a treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity.
  • the drug is approved for use in adults with a body mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater (overweight) who have at least one weight-related condition such as hypertension, type 2 diabetes, or high cholesterol (dyslipidemia).
  • GLP-1 analogues such as liraglutide and exenatide
  • liraglutide and exenatide have initially been used as diabetes type-2 medication, but successful weight loss trials have been performed where patients lost 8 kg more after one year on the highest dose of liraglutide; compared to the placebo group which lost 2 kg.
  • safety concerns exist regarding these drugs chiefly regarding suggested increased risk of developing pancreatic cancer.
  • the FDA still approves the use of liraglutide but encourages both prescribers and patients to report possible side effects.
  • Orlistat Xenical ®
  • Orlistat liraglutide
  • Orlistat is a semi-reversible and local inhibitor of gastric and pancreatic lipases in the Gl tract and acts as an antiobesity drug by preventing intestinal absorption of dietary fats (i.e. reducing energy intake).
  • the fraction of the dose absorbed of the highly lipophilic orlistat (log P 8.5) is low ( ⁇ 3%) and accordingly the plasma exposure is low ( ⁇ 5 ng/ml).
  • orlistat is available in a conventional relative rapid release oral dosage form.
  • orlistat although safe, is associated with some side-effects that severely hamper compliance.
  • about 25% or more of the patients complain about Gl side-effects including diarrhea, oily spotting and fecal urgency.
  • This in conjunction with the rather modest effect on weight (Best case scenario: 10% relative weight loss versus placebo 6% relative weight loss, makes orlistat in this conventional and relative rapid release dosage form unattractive for the vast majority of obese patients.
  • FDA clearly stated that orlistat is safe and has clinical benefit.
  • Acarbose (Glucobay®) is a competitive a-glucosidase and pancreatic a-amylase inhibitor, which inhibits the hydrolysis of oligosaccharides during Gl luminal digestion of a meal.
  • Acarbose has hydrophilic properties (log P -8.1) and consequently low intestinal permeability, low fraction dose absorbed ( ⁇ 5%), low bioavailability and systemic exposure of acarbose.
  • Acarbose available in conventional immediate release dosage form, is currently used as a diabetic drug, mainly in Asia, but only scarcely in Western countries. It has not been approved for treatment of obesity.
  • Gl tolerability problems mainly flatulence, diarrhea as well as Gl and abdominal pains
  • Miglitol is FDA approved and available in several countries, whereas voglibose is approved only in Japan.
  • Acarbose, miglitol and voglibose lowers HbA1c to more or less the same extent, with slightly different side effect.
  • Miglitol is absorbed to 100% and is excreted though the kidneys; whereas voglibose is, in similarity to acarbose, only negligibly absorbed.
  • Voglibose most probably due to its low dose (0,2 mg voglibose / meal is a common dose) shows lower frequency of Gl side effects compared to acarbose; but does not decrease rate of gastric emptying. So far available studies indicate that all three a- glucosidase inhibitors are safe with no systemic effects. There is also a plethora (>1200 compounds) of identified plant compounds that show varying a-glucosidase inhibitory effects. Acarbose stands out as it is by far the most clinically used and investigated compound, is approved worldwide and its patent has expired.
  • the present inventors have found that it is possible to follow a weight loss program involving treatment with anti-obese drugs or anti-overweight drugs with a treatment with acarbose and orlistat in combination and at a lower dose than used if acarbose and orlistat are used in the treatment of overweight.
  • the present invention is a development of the invention described in Applicant's patent application published as WO 2016/097170. It relates to a modified release composition of acarbose and orlistat present in the composition in three different parts with different release pattern.
  • the present invention relates to the use of a composition comprising orlistat and acarbose in body weight management to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 6% within a 6-month period such as ⁇ 3% within a 3-month period of the body weight resulting after the subject has ended treatment with a weight-lowering drug substance.
  • the subject is human.
  • Administration of the composition to the subject may start when the treatment with said weightlowering drug substance terminates, or it may start from 1 to 2 weeks before the treatment with said weight-lowering drug substance terminates, or it may start from 1 to 4 weeks after the treatment with said weight-lowering drug substance terminates.
  • the composition is designed for oral administration.
  • a daily dose of orlistat is from 30 mg to 270 mg such as from 60 mg to about 270 mg, from 90 mg to about 270 mg, such as 30 mg, 60 mg, 90 mg, 180 mg or 270 mg for an adult.
  • a daily dose of acarbose is from 10 mg to about 150 mg such as from 10 mg to about 120 mg, from 20 mg to about 150 mg, from 30 mg to about 150 mg, from 10 mg to 90 mg, such as 10 mg, 20 mg, 30 mg, 60 mg or 90 mg.
  • compositions may also be used to obtain health gain that may not directly be related to weight.
  • the weight ratio between orlistat and acarbose in the composition is in a range of from 2:1 to 4:1 such as 3:1.
  • composition comprising acarbose and orlistat is administered for a time period of at least 2 weeks such as from about 2 weeks to about 1 year such as from about 2 weeks to about 9 months, from about 2 weeks to about 6 months, from about 2 weeks to about 5 months, from about 2 weeks to about 4 months, from about 2 weeks to about 3 months, from about 2 weeks to about 2 months.
  • the intestine will need to acclimatize to acarbose.
  • Such a patient needs to start with a low dose of orlistat/acarbose to prepare the intestine. After a period of two weeks, a weight trajectory and side-effects can be evaluated and adjustment of the dose can take place.
  • the daily dose of orlistat may initially be from 90 to 270 mg in a time period of from 2 to 4 weeks of treatment followed by a daily dose of orlistat as disclosed herein such as, e.g., from 60 to 180 mg.
  • the daily dose of acarbose may initially be from 30 to 90 mg in a time period of from 2 to 4 weeks of treatment followed by a daily dose of acarbose as disclosed herein such as, e.g., from 20 to 60 mg.
  • compositions for use according to the invention are designed for oral administration and are designed to release orlistat and acarbose at suitable locations in the gastrointestinal tract.
  • a composition suitable for may comprise granules, spheres or pellets.
  • the obese or overweight subjects have a BMI of 25 kg/m 2 or more such as 27 kg/m 2 , 29 kg/m 2 or more or 30 kg/m 2 or more.
  • Overweight subjects have a BMI of 25 kg/m 2 or more such as from 25 kg/m 2 to less than 30 kg/m 2
  • obese subjects have a BMI of 30 kg/m 2 or more.
  • suitable compositions are those, wherein orlistat is in micronized form, i.e. , with an average particle size below 50 microns such as below 20 microns such as below 10 microns.
  • orlistat and enteric polymers may react in an undesired manner and, accordingly, when an enteric polymer is present in the composition, orlistat should be protected from direct contact with the enteric polymer. This may be done by use of a protective polymer such as a polymer selected from cellulose, cellulose derivatives, and hydroxypropyl methylcellulose.
  • Such a composition is designed in such a manner that i) part G1 is designed to release a part of the total dose of acarbose in the stomach, ii) part G2A is designed to release a part of the total dose of acarbose in duodenum and jejunum; the release should be relatively fast, as acarbose should be available to exert their effect in duodenum and jejunum, iii) part G2B is designed to release a part of the total dose of orlistat in duodenum and jejunum; the release should be relatively fast, as orlistat should be available to exert their effect in duodenum and jejunum, and iv) part G3 is designed to release of a part of the total dose of orlistat in duodenum and jejunum. Part b) and c) may be combined to part G2.
  • composition suitable for use according to the invention may be a composition wherein G1 is in the form of inert cores coated with a composition comprising acarbose, G2A and G2B are combined to G2 and G2 is in the form of inert cores coated onto which acarbose and orlistat are applied and then provided with a coating with a protective polymer followed by coating with an enteric coating, and G3 is in the form of uncoated granules.
  • a protective polymer is typically present in a concentration of at least 10% w/w such as in a range of from 10-20% w/w, from 12 to 20% w/w, from 13 to 20% w/w, from 13.5 to 20% w/w based on the total weight of G2.
  • a composition for use according to the invention may comprises modified release granules, spheres or pellets comprising from 30 to 50% w/w of micronized orlistat, from 35 to 60% w/w of microcrystalline cellulose and from 10 to 18% w/w of polysorbate 80 based on the total weight of the modified release granules, spheres or pellets.
  • part G3 comprises modified release granules, spheres or pellets comprising from 30 to 50% w/w of micronized orlistat, from 35 to 60% w/w of microcrystalline cellulose and from 10 to 18% w/w of polysorbate 80, based on the total weight of G3.
  • a composition for use according to the invention has i) a concentration of acarbose in the first part G1 is in a range of from 25% w/w to about 50% w/w such as from about 30% w/w to about 45% w/w or about 40% w/w based on the total weight of part G1 , ii) a concentration of acarbose in the second part G2A or G2 is in a range of from about 0.5% w/w to about 4.5% w/w such as from about 1% w/w to about 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/w to about 3.5% w/w, from about 2.5% w/w to about 3.25% w/w or about 3% w/w based on the total weight of G2A or G2, whichever is relevant, iii) a concentration of orlistat in part G2B or G2 is in a
  • the composition may comprise modified release granules, spheres or pellets containing from 35 to 60% w/w of cellulose or a cellulose derivative such as microcrystalline cellulose based on the total weight of the modified release granules, spheres or pellets.
  • the present invention relates to weight control management.
  • weight control management in the present context is a treatment for stabilizing a sustained healthy weight loss that may be slightly less than the potentially initial greater weight loss achieved from other drug products, but at a healthier and long-term slowly decreasing level.
  • Weight control management follows treatment of an obese or overweight subject with a weightlowering composition.
  • a weightlowering composition may be any known weight-lowering composition or a very low calorie diet, or it may be a composition comprising orlistat and acarbose wherein orlistat and acarbose is used in a daily dose that is higher than that used in weight control management.
  • Weight control management involves the use of a composition comprising orlistat and acarbose in body weight management to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 6% within a 6-month period such as ⁇ 3% within a 3-month period of the body weight resulting after the subject has ended treatment with a weight-lowering drug substance.
  • the composition is typically administered from 1 to 3 times daily resulting in a daily dose of orlistat of from 30 mg to 270 mg such as from 60 mg to about 270 mg, from 90 mg to about 270 mg, such as 30 mg, 60 mg, 90 mg, 180 mg or 270 mg for an adult, and a daily dose of acarbose of from 10 mg to about 150 mg such as from 20 mg to about 150 mg, from 30 mg to about 150 mg, from 10 mg to 90 mg, such as 10 mg, 20 mg, 30 mg, 60 mg or 90 mg.
  • the daily dose of orlistat/acarbose when a used for reduction of body weight is typically 120 mg/40 mg, 150 mg/50 mg or 180/60 given three times daily.
  • the weight control management of the present invention using a composition comprising orlistat and acarbose will: 1 ) gently triggers the satiety system, and 2) mildly decreases the uptake of fat and carbohydrates from the jejunum.
  • This treatment can start adjacent to other overweight treatments and is a way to maintain the weight loss achieved, or only slightly gain weight, avoiding the rebound effect. It is a way to combine another weight decrease treatment with this treatment - and thereby maintaining the lower weight.
  • the present invention provides a method for body weight management, the method comprises treating a subject with acarbose and orlistat to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 6% within a 6-month period or ⁇ 3% within a 3-month period from the body weight resulting after the subject has been treated with a weightlowering drug substance.
  • the weight control management treatment with a composition comprising orlistat and acarbose may start i) when the treatment with said weight-lowering drug substance terminates; ii) from 1 to 2 weeks before the treatment with said weight-lowering drug substance terminates; or iii) from 1 to 4 weeks after the treatment with said weight-lowering drug substance terminates.
  • the treatment period depends on how diligent the person is in changing lifestyle and diet habits.
  • the treatment period may be for at least 2 weeks such as for 4 weeks or more, 2 months or more, 4 months or more, 6 months or more, such as lifelong.
  • a break in the treatment is desirable in order to see whether the subject gains weight when the treatment is terminated. If the subject gains 3% or more in body weight but less than 6% within a time period of from 1 week to 6 months, then treatment with orlistat and acarbose is continued. If the gain in body weight is 6% or more a weight-lowering treatment should precede the treatment with orlistat and acarbose.
  • the treatment may also be for chronic use.
  • the invention also relates to the use of a composition comprising acarbose and orlistat in body weight management comprising treating a subject with acarbose and orlistat to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 3% within a 3- month period from the body weight resulting after the subject has been treated with a weightlowering drug substance.
  • the daily doses of orlistat and acarbose are lower compared to the doses used with orlistat and acarbose are used in a weight-lowering treatment.
  • Example 2 a synergistic effect has been demonstrated using a combination of orlistat and acarbose.
  • the synergy means that the two drug substance lead to more than an additive effect, which also indicates that lower doses may be applied, which should give even less side-effects.
  • the weight ratio between orlistat and acarbose should be in the range of from 2:1 to 4:1 such as 3:1.
  • a composition comprising orlistat and acarbose for use in weight control management is typically administered from 1 to 3 times daily resulting in a daily dose of orlistat of from 30 mg to 270 mg such as from 60 mg to about 270 mg, from 90 mg to about 270 mg, such as 30 mg, 60 mg, 90 mg, 180 mg or 270 mg for an adult, and a daily dose of acarbose of from 10 mg to about 150 mg such as from 20 mg to about 150 mg, from 30 mg to about 150 mg, from 10 mg to 90 mg, such as 10 mg, 20 mg, 30 mg, 60 mg or 90 mg.
  • the daily dose of orlistat/acarbose when a used for reduction of body weight is typically 120 mg/40 mg or 150 mg/50 mg given three times daily.
  • orlistat and acarbose is presented in the form of a composition.
  • a composition comprises granules, spheres and/or pellets comprising orlistat and/or acarbose.
  • the granules, spheres and/or pellets may be designed to release acarbose and/or orlistat in a modified manner.
  • modified release is intended to denote that the release of the active drug substance is manipulated by means of e.g. pharmaceutically acceptable excipients and/or coating materials; examples of coating materials that lead to a modified release are e.g. enteric coating materials;, which can be selected to release the active drug substance when pH is above a certain value such as e.g. pH above pH in the stomach; examples of pharmaceutically acceptable excipients that may lead to delayed release are e.g. celluloses or cellulose derivatives such as e.g. hydroxypropyl methylcellulose. Another way of obtaining a modified release may be by utilizing the water-soluble properties and/or pH-dependent solubility of the drug substances themselves.
  • a composition of the invention comprises granules, spheres or pellets. Some part of the composition is designed to avoid release of the active substances in the stomach (e.g. by coating of the granules, spheres or pellets, or by incorporating into the granules, spheres or pellets excipients that have pH-dependent release).
  • compositions comprising three or four different parts, wherein each part has a well-defined in vitro release pattern. However, the release rate from each part is based on simulations and in vitro investigations.
  • Compositions for use according to the present invention comprise also three or four parts, G1, G2A, G2B and G3; if it only contains three parts, then G2A and G2B are part G2.
  • the release rates of the APIs are designed so that acarbose is released both in the stomach and some parts of the small intestine via defined different formulation principles, whereas orlistat is released throughout the small intestines, but at different rates, until the end of jejunum.
  • acarbose is released both in the stomach and some parts of the small intestine via defined different formulation principles, whereas orlistat is released throughout the small intestines, but at different rates, until the end of jejunum.
  • the digested metabolites fatty acids, monoacylglycerols and hexose
  • the digested metabolites that is formed locally through local digestion will then act as ligands and stimulate the so- called gastro-intestinal brake effect.
  • RR denotes rapid release
  • DR denotes delayed release
  • PR denotes prolonged release.
  • the delayed release means that the release has been delayed, but when the release starts it may be rapid or prolonged.
  • the subscripts DC denoted delayed coating
  • GASTRIC denotes that the release starts in the stomach, but there may still be release of the drug substance after passage into and through the smail intestine until the end of jejunum
  • EC denotes an enteric coating, i.e. a coating with certain polymers that has a pH-cut off of about 4, i.e. they do not dissolve at acid pH and gradually begins to dissolve at about pH 4.
  • Polymers may be employed having a pKa value of about 5.5, i.e., they begin to dissolve at about pH 5.5. Accordingly, as the drug substances are not released at pH below 4, PROX-SI denotes that the release should start and mainly take place in the proximal small intestine, and INTESTINAL denotes that the release should take place in the first part of small intestine until the end of jejunum.
  • This invention provides an oral pharmaceutical modified-release (MR) composition that is designed to i) release a part of the total dose of acarbose in the stomach, but in a delayed manner in order to ensure that particles with acarbose will be well mixed with the food components and chyme in the postprandial stomach, ii) release a part of the total dose of acarbose and a part of the total dose of orlistat in duodenum and jejunum; this release should be relatively fast, as both acarbose and orlistat should be available to exert their effect in duodenum and jejunum, and iii) release of a part of the total dose of orlistat in duodenum and jejunum.
  • MR oral pharmaceutical modified-release
  • compositions for use according to the present invention can be used to prepare a composition for use according to the present invention.
  • Such formulation principles can be seen from WO 2016/097170 to which reference is made.
  • the inventors have developed a composition comprising acarbose and orlistat, wherein the composition contains individually distinct parts.
  • the composition may contain three or four different parts: a) a first part, G1 , comprising from about 45% w/w to about 65% w/w such as from about 50% w/w to about 65% w/w, from about 55% w/w to about 65% w/w or about 60% w/w of the total dose of acarbose, b) a second part, G2A, comprising from about 35% w/w to about 55% w/w such as from about 35% w/w to about 50% w/w, from about 35% w/w to about 45% w/w or about 40% w/w of the total dose of acarbose, c) a third part, G2B, comprising from about 50% w/w to about 85% w/w such as from about 55% w/w to about 80% w/w, from about 60% w/w to about 80% w/w, from about 65% w/w to about 75%
  • the combined part is called G2.
  • the release patterns of the distinct parts are different as the individual parts are designed to release acarbose and orlistat in the different parts of the gastrointestinal tract.
  • the concentration of acarbose in the first part G1 is in a range of from 25% w/w to about 50% w/w such as from about 30% w/w to about 45% w/w or about 40% w/w based on the total weight of part G1 .
  • the concentration of acarbose in the second part G2A or G2 is in a range of from about 0.5% w/w to about 4.5% w/w such as from about 1% w/w to about 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/w to about 3.5% w/w, from about 2.5% w/w to about 3.25% w/w or about 3% w/w based on the total weight of G2A or G2, whichever is relevant.
  • the concentration of orlistat in the second part G2B or G2 is in a range of from 5% w/w to about 30% w/w such as from about 10% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, from about 12% w/w to about 20% w/w or about 15.5% w/w based on the total weight of G2B or G2, whichever is relevant.
  • the concentration of orlistat in the third (or fourth part) G3 is in a range of from 20% w/w to about 50% w/w such as from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, from about 35% w/w to about 45% w/w or about 40% w/w based on the total weight of G3.
  • the enteric polymer contained in G2 may have had a certain negative effect on the in vivo release of orlistat (and/or acarbose) from G2 (G2A, G2B). It turned out that the desired release in vivo could be obtained by minimizing direct contact between the drug substances and the enteric polymer.
  • G2 When G2 (G2A, G2B) is in the form of granules, spheres or pellets the direct contact between the drug substances and the enteric polymer can be minimized by coating the granules, spheres or pellets (before admixing or coating with an enteric polymer) with a protective layer. It has been found that the protective layer should have a certain thickness in order to ensure that the active substances in the G2 granule do not come into direct contact with the enteric polymer.
  • the thickness is expressed as the concentration of protective layer in the final G2 (G2A, G2B) part and it should be in a concentration of at least 10% w/w such as in a range of from 10-20% w/w, from 12 to 20% w/w, from 13 to 20% w/w, from 13.5 to 20% w/w based on the weight of G2 (G2A, G2B).
  • the in vivo release could be optimized by using orlistat in micronized form. Orlistat has a very poor water solubility (less than 0.001 g/ml) and using orlistat in micronized form increase the surface area and thereby enhances the rate of water solubility. Also, the use of a surfactant to ease the contact between orlistat and the fluid in the gastrointestinal tract had positive impact on the release rate in vivo.
  • the G3 part of the composition is intended to release orlistat in a delayed manner such that orlistat is effective in the proximal intestine.
  • orlistat is used in micronized form and the concentration of orlistat in this part should be much smaller than originally envisaged in WO 2016/097170.
  • a composition according to the invention comprises a part G3, which comprises modified release granules, spheres or pellets comprising orlistat, wherein the modified release granules, spheres or pellets contains from 30 to 50% w/w of micronized orlistat based on the total weight of G3, the modified release granules, spheres or pellets comprising orlistat.
  • the granules, spheres or pellets of G3 comprises from 35 to 60% w/w of cellulose or a cellulose derivative such as microcrystalline cellulose.
  • the present invention also provides compositions as described herein such a composition described above.
  • the G1 part of the composition is designed to release acarbose in a prolonged manner.
  • the prolonged release is obtained by providing a G1 part that contains acarbose and a prolonged release polymer or a lipid.
  • the prolonged release polymer typically has a poor water-solubility, i.e.
  • hydrophobic polymer it is a hydrophobic polymer, and may be selected from the group consisting of ethylcellulose, acrylates or acrylic acid derivatives, gelatin, coating agent selected from the group consisting of copolymers based on polymethacrylic acid and methacrylates, ethyl acrylate and methyl acrylate, copolymers of acrylic and methacrylic acid esters, hydroxypropyl methylcellulose phthlate, cellulose acetate phthalate, polyvinyl acetate phthalate or mixtures thereof.
  • the lipid may be selected from fatty acids and/or esters, fatty alcohols, cetyl alcohol, stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, Castor oil, preferably solid at room temperature, most preferably hydrogenated vegetable oil.
  • the hydrophobic polymer or lipid is typically present in G1 in a concentration of from about 10% to about 50% w/w such as from about 15% to about 45% w/w, from about 20 to about 40% w/w, from about 15% to about 25% of the total weight of G1.
  • the hydrophobic polymer or lipid may be substituted by or supplemented with hyd roxypropyl methylcel I u lose or a wax such as, e.g., glycerol monostearate, white wax, carnauba wax, stearyl alcohol, stearic acid, polyethylene glycol and triglycerides or mixtures thereof.
  • a wax such as, e.g., glycerol monostearate, white wax, carnauba wax, stearyl alcohol, stearic acid, polyethylene glycol and triglycerides or mixtures thereof.
  • Hydroxypropylmethylcellulose or wax is typically present in G1 in a concentration of from about 3% w/w to about 50% w/w such as from about 3% w/w to about 45% w/w, from about 3% w/w to about 40% w/w, from about 3% to about 35% w/w, from about 3% to about 30% w/w, from about 3% to about 25% w/w, from about 4% w/w to about 20% w/w, from about 4% w/w to about 15% w/w, from about 4.5% w/w to about 10% w/w or from about 5% to about 9.5% w/w based on the total weight of G1.
  • the concentration range is from about 10% to about 50% w/w such as from about 15% to about 45% w/w or from about 20 to about 40% w/w of the total weight of G1.
  • the concentration of acarbose in the first part G1 is in a range of from 25% w/w to about 50% w/w such as from about 30% w/w to about 45% w/w or about 40% w/w based on the total weight of part G1
  • G1 may be prepared based on a neutral core such as e.g., a microcrystalline cellulose core onto which a coating composition is applied containing acarbose.
  • a neutral core such as e.g., a microcrystalline cellulose core onto which a coating composition is applied containing acarbose.
  • the G2 part of the composition is designed to have a delayed release of acarbose and orlistat, but once release starts then it is relatively rapid.
  • This release pattern is obtained by combining the drug substances with one or more surfactants (especially in order to increase the solubility of orlistat) and an enteric polymer, i.e., a polymer that has a pH dependent solubility such that it is not soluble at low pH (normally at pH 4 or less), but soluble at neutral/alkaline pH.
  • the polymer may be incorporated into the formulation of G2 or it may be used as a coating material to coat the G2 formulation. As mentioned herein before, it is necessary to minimize any direct contact between the drug substances and the enteric polymer.
  • Suitable polymers for use as protective polymers include cellulose or cellulose derivatives such as hydroxypropyl methylcellulose or other film-forming polymers.
  • orlistat must be used in micronized form in order to achieve a desired release in vivo. Accordingly, average particle size of orlistat should be 50 microns or below such as 20 microns or below, 10 microns or below or 5 microns or below.
  • the surfactant is typically selected from the group consisting of anionic, cationic or non-ionic surfactant.
  • Non-ionic are e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalcohol.
  • Anionic surfactants include docusate sodium and sodium lauryl sulphate.
  • Cationic surfactants include e.g., benzalkonium chloride, benzethonium chloride and cetrimide.
  • the total concentration of surfactants is typically present in G2 in a concentration of from about 0.5% to about 30% w/w of the total weight of G2.
  • the concentration is from about 1% w/w to about 10% w/w such as from about 1% w/w to about 8% w/w, from about 1% w/w to about 5% w/w based on the total weight of G2.
  • the enteric polymer may also be a coating agent selected from the group consisting of copolymers based on polymethacrylic acid and methacrylates, ethyl acrylate and methyl acrylate, copolymers of acrylic and methacrylic acid esters, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinyl acetate phthalate or mixtures thereof, such as that which is commercially available from Shin-Etsu and Seppic under the name Aqoat ® AS-LG (hypromellose acetate succinate).
  • Aqoat ® AS-LG hyperromellose acetate succinate
  • the enteric polymer is typically an acrylate or acrylic acid polymer or co-polymer.
  • the acrylic polymer may comprise one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic polymer may be used in the form of an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the tradename Eudragit ® or from Colorcon under the tradename Acryl-EZE ® .
  • the acrylic coating may comprise a mixture of two acrylic resin lacquers commercially available from Evonik under the tradenames Eudragit ® RL 30 D and Eudragit ® RS 30 D, respectively.
  • Eudragit ® RL 30 D and Eudragit ® RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :2Q in Eudragit ® RL30 D and 1 :40 in Eudragit ® RS 30 D.
  • Eudragit ® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit ® RL/RS dispersions may be mixed together in any desired ratio in order to ultimately obtain a modified release formulation having a desirable dissolution profile.
  • the enteric polymer is typically present in a concentration of from about 15 to about 50% w/w based on the total weight of the G2 formulation. It is preferred that the concentration is from about 20% w/w to about 40% w/w such as from about 15% w/w to about 40% w/w, from about 15% w/w to about 35% w/w, from about 15% w/w to about 30% w/w, from about 20 to about 25% w/w based on the total weight of G2.
  • the concentration of the protective polymer in G2 (G2A, G2B) part should be at least 10% w/w such as in a range of from 10-20% w/w, from 12 to 20% w/w, from 13 to 20% w/w, from 13.5 to 20% w/w based on the total weight of G2 (G2A, G2B).
  • the concentration of acarbose in the second part G2A or G2 is in a range of from about 0.5% w/w to about 4.5% w/w such as from about 1% w/w to about 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/w to about 3.5% w/w, from about 2.5% w/w to about 3.25% w/w or about 3% w/w based on the total weight of G2A or G2, whichever is relevant.
  • the concentration of orlistat in the second part G2B or G2 is in a range of from 5% w/w to about 30% w/w such as from about 10% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, from about 12% w/w to about 20% w/w or about 15.5% w/w based on the total weight of G2B or G2, whichever is relevant.
  • the G3 part is designed to release orlistat in a prolonged manner.
  • Orlistat may be release at a low degree already in the stomach.
  • Orlistat is very poor water-soluble and in order to achieve the desired release, orlistat is combined with one or more surfactants.
  • the surfactant may be one or more of those mentioned above under G2.
  • the surfactant is present in G3 in a concentration from about 1% to about 30% w/w of the total weight of the G3 formulation. Preferably, it is present from about 2% to about 20% w/w, from about 3% to about 20% w/w from about 5% w/w to about 20% w/w, from about 10% w/w to about 15% w/w.
  • orlistat must be used in micronized form in order to achieve a desired release in vivo. Accordingly, average particle size of orlistat should be 50 microns or below such as 20 microns or below, 10 microns or below or 5 microns or below.
  • the release of orlistat from G3 can be obtained by incorporation of a water-soluble or water-swellable polymer such as hyd roxypropyl methylcel I u lose or other cellulose derivatives like e.g. methylcellulose, carboxymethyl cellulose, hyd roxypropylcel I u lose , microcrystalline cellulose or the like.
  • a water-soluble or water-swellable polymer such as hyd roxypropyl methylcel I u lose or other cellulose derivatives like e.g. methylcellulose, carboxymethyl cellulose, hyd roxypropylcel I u lose , microcrystalline cellulose or the like.
  • Such a water-soluble polymer is typically incorporated into the G3 formulation in a concentration of from about 35 to about 60% w/w such as from about 35% w/w to about 55% w/w, from about 35% to about 50%, from about 40% w/w to about 50% w/w based on the total weight of G3.
  • the concentration may be from about 70 to about 90% w/w based on the total weight of G3.
  • the concentration is from about 40 to about 50% w/w.
  • the concentration of orlistat in the third (or fourth part) G3 is in a range of from 20% w/w to about 50% w/w such as from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, from about 35% w/w to about 45% w/w or about 40% w/w based on the total weight of G3.
  • the G1 , G2 (or G2A, G2B) and G3 parts may also contain other pharmaceutically acceptable ingredients selected from those mentioned herein.
  • a final composition G1 , G2 (or G2A, G2B), and/or G3 may be admixed with one or more pharmaceutically acceptable excipient or G1 , G2 (or G2A, G2B), and/or G3 may be coated e.g., with a film coating or with a coating that hinders or reduces negative impact of one part to another part.
  • the part G1 of the composition may be in the form of granules, spheres, pellets, minitablets etc. or part G1 is incorporated into a two-layer tablet, where part G1 is contained in one of the two layers.
  • the layer containing part G1 may be provided with a delayed release coating.
  • Part G2, or G2A and G2B, of the composition may be in the form of granules, spheres, pellets, minitablets etc. containing an enteric polymer or provided with an enteric coating, or G2, or G2A and G2B, is incorporated into a two-layer tablet, where part G2, or G2A and G2B, is contained in one of the two layers and the layer containing part G2, or G2A and G2B, is provided with an enteric coating.
  • Part G3 may be in the form of granules, spheres, pellets, minitablets etc. or it is contained in a two- layer tablet, wherein part G3 is contained in one of the two layers.
  • the final modified-release composition according to the invention may be in the form of a multiple- unit tablet, a bi-layer multiple-unit tablet, a coated tablet, a multiple-unit capsule or a multiple-unit oral powder.
  • G1 , G2, or G2A and G2B, and G3 are in the form of pellets, granules, spheres or the like, and the modified-release composition according to the invention is in the form of a multiple-unit tablet, capsule, sachet or powder.
  • G1 is in the form of inert cores coated with a coating composition comprising acarbose;
  • G2 is in the form of inert cores coated onto which the drug substances are applied and then provided with a protective coating followed by coating with an enteric coating.
  • G3 is in the form of uncoated granules.
  • G1 , G2 or G3 formulations may be included in the G1 , G2 or G3 formulations.
  • compositions should be administered to the subject at the same time.
  • compositions of the invention are provided.
  • the present invention also provides a composition comprising two or more parts with different release pattern.
  • the parts are denoted G2 or G2B and G3.
  • a composition contains i) a part G2B, comprising from about 50% w/w to about 85% w/w such as from about 55% w/w to about 80% w/w, from about 60% w/w to about 80% w/w, from about 65% w/w to about 75% w/w, from about 68% w/w to about 75% w/w, from about 72% w/w to about 73% w/w such as about 72.2% w/w of the total dose of orlistat, and ii) a part, G3, comprising from about 15 to about 50% w/w such as from about 20% w/w to 40% w/w, from about 25% to about 35% w/w, from about 25% to about 32% w/w, from about 27% w/w to about 28% w/w or about
  • the concentration of orlistat in the part G2B is in a range of from 5% w/w to about 30% w/w such as from about 10% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, from about 12% w/w to about 20% w/w or about 15.5% w/w based on the total weight of G2B.
  • the concentration of orlistat in the part G3 is in a range of from 20% w/w to about 50% w/w such as from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, from about 35% w/w to about 45% w/w or about 40% w/w based on the total weight of G3.
  • composition may further contain a part G1 and G2A as described herein and part G2A and G2B may be mixed for form part G2.
  • the invention also provides a composition containing three or four different parts: a) a first part, G1 , comprising from about 45% w/w to about 65% w/w such as from about 50% w/w to about 65% w/w, from about 55% w/w to about 65% w/w or about 60% w/w of the total dose of acarbose, b) a second part, G2A, comprising from about 35% w/w to about 55% w/w such as from about 35% w/w to about 50% w/w, from about 35% w/w to about 45% w/w or about 40% w/w of the total dose of acarbose, c) a third part, G2B, comprising from about 50% w/w to about 85% w/w such as from about 55% w/w to about 80% w/w, from about 60% w/w to about 80% w/w, from about 65% w/
  • the concentration of acarbose in the first part G1 is in a range of from 25% w/w to about 50% w/w such as from about 30% w/w to about 45% w/w or about 40% w/w based on the total weight of part G1 .
  • the concentration of acarbose in the second part G2A or G2 is in a range of from about 0.5% w/w to about 4.5% w/w such as from about 1% w/w to about 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/w to about 3.5% w/w, from about 2.5% w/w to about 3.25% w/w or about 3% w/w based on the total weight of G2A or G2, whichever is relevant.
  • the concentration of orlistat in the second part G2B or G2 is in a range of from 5% w/w to about 30% w/w such as from about 10% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, from about 12% w/w to about 20% w/w or about 15.5% w/w based on the total weight of G2B or G2, whichever is relevant.
  • the concentration of orlistat in the third (or fourth part) G3 is in a range of from 20% w/w to about 50% w/w such as from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, from about 35% w/w to about 45% w/w or about 40% w/w based on the total weight of G3.
  • Orlistat may be prepared from biological material ( Streptomyces toxytricin) or it may be prepared synthetically or semi-synthetically. According to the literature, orlistat appears in two different crystal forms, Form I and Form II. The melting point of Form I and Form II is 44°C and 43°C respectively. The product marketed by Roche under the name Xenical ® capsules in Sweden contains Form II. No salt forms of orlistat seem to exist. It is practically insoluble in water.
  • orlistat covers the above-mentioned chemical structure as well as any optical isomer thereof as well as any crystal form, any polymorph, any hydrate, any pharmaceutically acceptable or any prodrug thereof.
  • the reduced lipid digestion caused by orlistat increases gastric emptying (food is delivered faster to the duodenum). If the meal is high in fat, diarrhoea might occur within 30 min from meal initiation. This diarrhoea is most probably due to the fact that food in the stomach normally triggers emptying of the colon. This signal, in combination of supra-normal amounts of fat in the faeces from previous meals (which leads to less water absorbed during colon transit), may cause the diarrhoea. Possibly, high fat meals will further augment the stomach-to-colon signal, thereby aggravating the situation.
  • the fatty acid signal to CCK will be weaker, and less bile will be secreted, which further decreases fat digestion.
  • Acarbose may be prepared from biological material (Actinoplanes) or it may be prepared synthetically or semi-synthetically. No information about the crystal form of acarbose could be found in the literature. However, some sources indicate that acarbose may be amorphous and no salt forms of acarbose seems to exist. According to Ph. Eur. it is very soluble in water.
  • acarbose covers the above-mentioned structure as well as any optical isomer thereof as well as any crystal form, any polymorph, any hydrate, any pharmaceutically acceptable or any prodrug thereof.
  • Acarbose (Glucobay ® ) is a competitive a-glucosidase and pancreatic a-amylase inhibitor, which inhibits the hydrolysis of oligosaccharides during Gl luminal digestion of a meal.
  • Acarbose is currently used as a diabetic drug, mainly in Asia, but only scarcely in Western countries. By inhibiting the luminal digestion and subsequent absorption of carbohydrates, the concentrations of glucose in blood sugar increases slower postprandially, and the patient's insulin need is reduced.
  • the low intestinal permeability of acarbose leads to less than 5% of the drug being absorbed after oral administration.
  • Figure 1 show details regarding the clinical study described in Example 2 herein and the results thereof.
  • Figure 2 shows relative weight loss during the 26-week study period, see Example 2.
  • Figure 3 shows the proportion of participants losing more than 5% and 10% weight. More patients in the active treatment groups had lost 5% or more (p ⁇ 0.0001 for both active treatment vs placebo) and 10% or more (p ⁇ 0.1 for both active treatment groups vs placebo) at week 26.
  • Figure 4 shows simulated weight loss at week 52, based on weight loss rate between baseline and week 14, and between week 14 and 26 (Mean with 95% confidence intervals).
  • Figure 5 shows the correlation between relative weight loss and change in the RAND-36 item health transition (from baseline to week 26) in the three arms.
  • Example 1 A composition comprising three parts, G1, G2 and G3 was prepared:
  • EMP16-02-60/20 modified-release capsules containing orlistat 30 mg/unit and acarbose 10 mg/unit is described below:
  • EMP16-02-60/20 modified-release capsules containing orlistat 60 mg/unit and acarbose 20 mg/unit is described below:
  • EMP16-02-90/30 modified-release capsules containing orlistat 90 mg/capsule and acarbose 30 mg/unit is described below:
  • composition of G1 granules containing acarbose 391.5 mg/g is described below:
  • composition of G3 granules containing 400.0 mg/g is described below:
  • the secondary objectives were: i) To assess the effect of two different doses of EMP16-02 (120 mg 0/40 mg A and 150 mg 0/50 mg A) on relative and absolute body weight loss during a 26-week period of oral treatment as compared to placebo; ii) To assess the effect of two different doses of EMP16-02 (120 mg 0/40 mg A and 150 mg 0/50 mg A) on other anthropometric characteristics during a 26-week period of oral treatment as compared to placebo; iii) To assess the effect of two different doses of EMP16-02 (120 mg 0/40 mg A and 150 mg 0/50 mg A) on satiety and meal pattern during a 26-week period of oral treatment as compared to placebo; iv) To assess the effect of two different doses of EMP16-02 (120 mg 0/40 mg A and 150 mg 0/50 mg A) on fasting insulin, glucose metabolism markers, lipid metabolism markers and inflammation markers during a 26-week period of oral treatment as
  • BMI body mass index
  • the primary endpoint was the relative % change from baseline in body weight after 26 weeks of treatment with EMP16-02 (120 mg 0/40 mg A) as compared to placebo.
  • EMP16-02 120/40 2 capsules of EMP16-02 60/20 are used.
  • EMP16-02 Patients randomised to EMP16-02 started with a run-in period of 6 weeks during which the dose was sequentially increased. From week 7, all patients will have reached their final intended dose and a 20-week treatment and observation period started.
  • the run-in phase started at a dose of 60 mg O and 20 mg A TID, which sequentially was increased with 30 mg 0/10 mg A every two weeks until the target doses of 120 mg 0/40 mg A TID (for the lower dose group) and 150 mg 0/50 mg A TID (for the higher dose group) were reached.
  • the dosing regimen was as follows:
  • Placebo treatment consisted of matching oral capsules. Placebo and EMP16-02 capsules needed to be taken TID together with three daily meals.
  • Visit 5 week 26
  • the patients would take the last dose during breakfast at the clinic.
  • Visit 6 was a safety follow up visit.
  • Visit 7 was a 6 months follow-up visit for consenting patients who had completed the 26-week treatment period with active EMP16-02 treatment (120 mg 0/40 mg A and 150 mg 0/50 mg A) or placebo.
  • Weight other anthropometric measurements (BMI, waist circumference, sagittal diameter, bioimpedance), blood sampling for fasting lipid metabolism, glucose metabolism and inflammations markers, blood pressure, questionnaires (meal pattern, GSRS, satiety and craving, activity and sleep and health and quality of life [RAND-36]), drop-out rate (assessed both in terms of safety and efficacy).
  • Meal pattern, satiety and craving and health and quality of life (RAND-36) questionnaires were analyzed using the Wilcoxon Rank Sum test.
  • the GSRS questionnaire was analyzed using ANCOVA while the activity and sleep questionnaire was analyzed using a Chi-square test.
  • the drop-out rate (overall and Gl-related) following treatment with EMP16-120/40 or EMP16-150/50 as compared to placebo was analyzed using Chi-square test without continuity correction.
  • Mean absolute change from baseline in sagittal diameter was -1.89 cm in the EMP16-150/50 group and -0.49 cm in the placebo group at week 26.
  • Mean relative and absolute change from baseline in percentage body fat was -5.4% and -2.21 in the EMP16- 150/50 group and -0.3% and -0.19 in the placebo group, respectively.
  • Health-related quality of life based on the RAND-36 health survey improved more in the active treatment groups compared to the placebo group between baseline and week 26.
  • patients in the EMP 150/50 group improved significantly more than patients in the placebo group in terms of bodily pain, energy/fatigue and emotional well-being.
  • Data are mean (SD) or n (%).
  • One participant was Asian and one was African American in the EMP16 120/40 group, and the remainder were white.
  • BMI body-mass index.
  • BP blood pressure.
  • HbA1c glycosylated haemoglobin A1c.
  • HDL high-density lipoprotein.
  • LDL low-density lipoprotein.
  • Table 2 Estimated changes in body weight from baseline to week 14 and week 26
  • SD Mean (SD) data and estimated difference (95% confidence interval) from the ITT analysis set with LOCF imputation.
  • ITT intention-to-treat population, everyone with at least one post first dose measurement.
  • LOCF last-observation-carried-forward.
  • SD standard deviation Analysed with ANCOVA with LCOF imputation of missing data. 1 Percentages of the populations losing >5% or >10% bodyweight were analysed using Chi 2 and are presented as the proportions of participants (%) and odds ratios.
  • Observed mean data (SD) and estimated difference (95% confidence intervals) are presented for the ITT analysis set without imputations. Analysis of covariance was performed with imputations using last observation carried forward (LOCF). Changes at weeks 7 and 14 during the trial are presented in the appendix.
  • HbA1 c glycosylated haemoglobin A1C.
  • HDL high density lipoprotein.
  • ITT intention-to-treat population.
  • LDL low density lipoprotein.
  • LOCF last-observation-carried-forward.
  • SD standard deviation.
  • Table 4 Questionnaires, absolute changes from baseline to week 26
  • Observed mean data (SD) and estimated difference (95% confidence intervals) are presented for the ITT analysis set without imputations. Analysis of covariance was performed with imputations using last observation carried forward (LOCF). Changes at weeks 7 and 14 during the trial are presented in the appendix.
  • GSRS gastrointestinal symptoms rating scale, where higher scores indicate increased intensity.
  • RAND-36 36-item short form health survey where higher score indicates better quality of life.
  • ALT Alanine Aminotransferase
  • AST Aspartate Aminotransferase
  • ALP Alkaline Phosphatase
  • GGT Gamma Glutamyl Transferase
  • Table A3 Questionnaires, baseline data [mean points (SD)]
  • Table A4 The primary outcome variable weight loss, relative change from baseline to weeks 14 and 26 in the Per Protocol population and a post-hoc imputation population.
  • Number of participants in PP were: 41 (EMP16-120/40), 41 (EMP16-150/50) and 40 (Placebo).
  • Number of participants in the PHIP were: 48 (EMP16-120/40), 50 (EMP16-150/50) and 51 (Placebo).
  • Glucose tolerance status was defined as diabetes when fasting blood glucose > 7.0 mmol/L and as prediabetes when fasting glucose was between 6.1 mmol/L and 7.0 mmol/L and was presented as n (%).
  • Gastroenteritis 1(2%) 1 0 0 0 0 1(1%) 1
  • Gastrointestinal infection 0 0 0 0 0 1(2%) 1 1(1%) 1
  • Dyspepsia 1(2%) 1 0 0 1(2%) 1 2(1%) 2 Encopresis 1(2%) 2 0 0 0 0 1(1%) 2 Flatulence 4(8%) 4 3(6%) 4 1(2%) 1 8(5%) 9 Food poisoning 0 0 0 0 1(2%) 1 1(1%) 1
  • Gastrointestinal motility disorder 1(2%) 1 0 0 0 0 1(1%) 1
  • Gastrooesophageal reflux disease 1(2%) 1 0 0 1(2%) 1 2(1%) 2
  • Musculoskeletal pain 1(2%) 1 0 0 0 0 1(1%) 1
  • Nervous system disorders 5(10% 7 2(4%) 2 5(10% 6 12(8% 15
  • Urticaria 1(2%) 1 0 0 0 0 1(1%) 1
  • Oropharyngeal pain 1(2%) 1 2(4%) 2 0 0 3(2%) 3
  • Alanine aminotransferase increased 1(2%) 1 1(2%) 1 0 0 2(1%) 2 Aspartate aminotransferase 1(2%) 1 1(2%) 1 0 0 2(1%) 2 increased
  • Knee operation 1(2%) 1 0 0 0 0 0 1(1%) 1
  • Skin neoplasm excision 1(2%) 1 0 0 0 0 0 1(1%) 1
  • Toe operation 1(2%) 1 0 0 0 0 1(1%) 1
  • the AE “back pain due to traffic accident” was coded with multiple MedDRA terms and is represented as separate AEs in the table n, number of subjects; m, number of events. Percentages are based on the number of subjects randomized. Baseline events (events that occurred prior to first dose) are omitted from summary.
  • NE Not evaluable. In cases of NE a warning occurred due to non-Chi 2 distribution. Subjects who miss one or several visits and who later re-enter the study were not considered dropouts until they missed all remaining visits.
  • 149 constituted the modified ITT population and were assessed for the primary endpoint, and 135 completed the 28-week trial period.
  • the PP population was comprised of 122 participants across treatment groups. In total, 111 women and 45 men were randomised in the trial. There were no important differences between the three groups at baseline (table 1).
  • a total of 191 AEs were reported by 101 (65%) of the 156 randomised participants with the three most common events being nasopharyngitis, diarrhoea and headache (table 5). Diarrhoea was reported only in the active treatment groups. Four of 52 participants (7-7%) in the EMP16-120/4Q group and 5 of 52 participants (9-6%) in the EMP16-150/50 group withdrew early from the trial due to Gl related AEs. In addition, 1 participant in the EMP-150/50 group withdrew consent to remain in the trial due to a COVID-19 infection. No participants in the placebo group withdrew due to an AE, whereas the overall withdrawal rate was comparable between the active treatment groups. Most AEs were mild or moderate in intensity. No deaths or serious AEs occurred during the trial. Compliance was high and no difference between the treatment groups was observed.
  • liver enzymes There were no clinically noteworthy changes in liver enzymes during the trial. A few individuals had a transient increase; however, these were not judged to be related to IMP according to the investigator, and the participants continued in the trial. There were no clinically relevant or statistically significant changes or differences in safety laboratory parameters or EGG during the trial (data not shown).
  • EMP16 was designed to encompass three contributing factors: (i) the mechanisms of action of orlistat and acarbose in their conventional dosage form on energy uptake; (ii) employment of a modified-release pattern to ensure that food- derived ligands are delivered to various appetite regulating checkpoints in the Gl tract in an appropriate manner; and (iii) improved tolerability.
  • Orlistat and acarbose in their conventional dosage forms are associated with frequent Gl side effects, which limit their popularity.
  • 15% of the participants receiving EMP16 reported diarrhoea whereas no participants in the placebo group did so, and more subjects (6-8%) in the EMP16 groups reported flatulence compared to the placebo group (2%). Since Gl events were recorded as AEs in the trial only if they were judged by the investigator as being severe or leading to withdrawal, some cases of minor or moderate Gl-events were not registered.
  • the results from the GSRS corroborate that the frequency of diarrhoea with EMP16 was greater than that in the placebo group, but the diarrhoea syndrome scores in both intervention groups were around 3 (mild discomfort).
  • the LOCF imputation method was prespecified in the protocol and has previously been recommended by regulatory authorities but is no longer regarded as optimal. A more conservative imputation method was added post-hoc, and comparable results were obtained.
  • the RAND-36 health questionnaire comprises 36 questions.
  • the questionnaire taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perception. It also includes a single item that provides an indication of perceived change in health. A low score indicates poor health-related quality of life while a high score indicates good health-related quality of life.
  • EMP16 did not induce any clinically relevant effects on fasting glucose metabolism markers, lipid metabolism markers or liver enzymes, had no apparent effect on the diabetic and prediabetic status of patients and no apparent effect on blood pressure compared to placebo, which is reasonably expected in a patient population with low prevalence of hypertension and with blood lipids and HbA1c within normal ranges as in the EP-002 study.
  • a method for body weight management comprises treating a subject with acarbose and orlistat to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 5% from the body weight resulting after the subject has been treated with a weight-lowering drug substance.
  • a method according to item 1 wherein the treatment with acarbose and orlistat starts from 1 to 2 weeks before the treatment with said weight-lowering drug substance terminates.
  • a method according to item 1 wherein the treatment with acarbose and orlistat starts from 1 to 4 weeks after the treatment with said weight-lowering drug substance terminates.
  • a method according to any one of the preceding items, orlistat and acarbose are administered in the form of one or more oral composition(s).
  • a daily dose of acarbose is from 10 mg to about 150 mg such as from 20 mg to about 150 mg, from 30 mg to about 150 mg, from 40 mg to about 150 mg, from 50 mg to about 150 mg, from 60 mg to about 150 mg or more such as from 90 mg to 150 mg, 90 mg or more, 120 mg or more or 150 mg or more.
  • composition comprises 90 mg orlistat/30 mg acarbose, 120 mg orlistat/40 mg orlistat or 150 mg orlistat/50 mg acarbose.
  • composition comprises granules, spheres or pellets.
  • composition comprises enteric coated granules, spheres or pellets comprising orlistat.
  • composition comprises enteric coated granules, spheres or pellets comprising acarbose.
  • composition comprises modified release granules, sphere or pellets.
  • composition comprises three or four different parts: a) a first part, G1 , comprising from about 45% w/w to about 65% w/w such as from about 50% w/w to about 65% w/w, from about 55% w/w to about 65% w/w or about 60% w/w of the total dose of acarbose, b) a second part, G2A, comprising from about 35% w/w to about 55% w/w such as from about 35% w/w to about 50% w/w, from about 35% w/w to about 45% w/w or about 40% w/w of the total dose of acarbose, c) a third part, G2B, comprising from about 50% w/w to about 85% w/w such as from about 55% w/w to about 80% w/w, from about 60% w/w to about 80% w/w/w
  • a method according to item 20 or 21 wherein the concentration of acarbose in the first part G1 is in a range of from 25% w/w to about 50% w/w such as from about 30% w/w to about 45% w/w or about 40% w/w based on the total weight of part G1 .
  • concentration of acarbose in the second part G2A or G2 is in a range of from about 0.5% w/w to about 4.5% w/w such as from about 1% w/w to about 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/w to about 3.5% w/w, from about 2.5% w/w to about 3.25% w/w or about 3% w/w based on the total weight of G2A or G2, whichever is relevant.
  • concentration of orlistat in part G2B or G2 is in a range of from 5% w/w to about 30% w/w such as from about 10% w/w to about 25% w/w, from about 10% w/w to about 20% w/w, from about 12% w/w to about 20% w/w or about 15.5% w/w based on the total weight of G2B or G2, whichever is relevant.
  • concentration of orlistat in part G3 is in a range of from 20% w/w to about 50% w/w such as from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, from about 35% w/w to about 45% w/w or about 40% w/w based on the total weight of G3.
  • part G2 comprises a protective polymer in a concentration of at least 10% w/w such as in a range of from 10-20% w/w, from 12 to 20% w/w, from 13 to 20% w/w, from 13.5 to 20% w/w based on the weight of G2.
  • G2A or G2B whichever is relevant.
  • composition comprises modified release granules, spheres or pellets comprising orlistat, wherein the modified release granules, spheres or pellets contains from 30 to 50% w/w of orlistat.
  • composition comprises orlistat in micronized form, i.e., with an average particle size below 50 microns such as below 20 microns such as below 10 microns.
  • composition comprises modified release granules, spheres or pellets containing from 35 to 60% w/w of cellulose or a cellulose derivative such as microcrystalline cellulose.
  • composition comprises modified release granules, spheres or pellets comprising from 30 to 50% w/w of micronized orlistat, from 35 to 60% w/w of microcrystalline cellulose and from 10 to 18% w/w of polysorbate 80.
  • composition as defined in any one of items 20-30.
  • Acarbose and orlistat for use in body weight management comprising treating a subject with acarbose and orlistat to reduce fluctuations in body weight so that the body weight of said subject stays within a range of ⁇ 10% from the body weight resulting after the subject has been treated with a weight-lowering drug substance.

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Abstract

La présente invention concerne un procédé de régulation du poids corporel, le procédé consistant à traiter un sujet avec de l'acarbose et de l'orlistat pour réduire les fluctuations du poids corporel de telle sorte que le poids corporel dudit sujet reste dans une plage de ± 6 % pendant une période de 6 mois, par exemple ± 3 % pendant une période de 3 mois par rapport au poids corporel obtenu après traitement du sujet à l'aide d'une substance médicamenteuse amaigrissante. Le traitement avec de l'acarbose et de l'orlistat commence lorsque le traitement avec ladite substance médicamenteuse amaigrissante se termine ou, alors, commence de 1 à 4 semaines avant la fin du traitement avec ladite substance médicamenteuse amaigrissante.
PCT/EP2022/063758 2021-05-21 2022-05-20 Utilisation d'une composition comprenant de l'orlistat et de l'acarbose pour obtenir une perte de poids prolongée WO2022243528A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102872062A (zh) * 2011-07-13 2013-01-16 鲁南制药集团股份有限公司 一种治疗或预防肥胖症以及代谢综合症的药物组合物
WO2016097170A1 (fr) 2014-12-17 2016-06-23 Empros Pharma Ab Composition à libération modifiée d'orlistat et d'acarbose pour le traitement d'obésité et de troubles métaboliques associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102872062A (zh) * 2011-07-13 2013-01-16 鲁南制药集团股份有限公司 一种治疗或预防肥胖症以及代谢综合症的药物组合物
WO2016097170A1 (fr) 2014-12-17 2016-06-23 Empros Pharma Ab Composition à libération modifiée d'orlistat et d'acarbose pour le traitement d'obésité et de troubles métaboliques associés

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Title
ANONIMOUS: "GLUCOBAY Product Monograph PRODUCT MONOGRAPH", 10 June 2010 (2010-06-10), pages 1 - 28, XP055857309, Retrieved from the Internet <URL:https://pdf.hres.ca/dpd_pm/00010798.PDF> [retrieved on 20211102] *
ANONIMOUS: "Orlistat Monograph for Professionals -Drugs", 15 February 2021 (2021-02-15), pages 1 - 11, XP055857308, Retrieved from the Internet <URL:https://www.drugs.com/monograph/orlistat.html> [retrieved on 20211102] *
JAIN SUYOGS ET AL: "Evaluation of efficacy and safety of orlistat in obese patients", vol. 15, no. 2, 1 January 2011 (2011-01-01), pages 99, XP055857388, ISSN: 2230-8210, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125014/pdf/IJEM-15-99.pdf> DOI: 10.4103/2230-8210.81938 *
NAKHAEE AKRAM ET AL: "Evaluation of effect of acarbose consumption on weight losing in non-diabetic overweight or obese patients in Kerman", JOURNAL OF RESEARCH IN MEDICAL SCIENCES, 1 May 2013 (2013-05-01), India, pages 391 - 394, XP055857408, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810572/pdf/JRMS-18-391.pdf> [retrieved on 20211103] *

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