CN117677374A

CN117677374A - Synergistic effect of orlistat and acarbose combination on weight loss, quality of life and reduction of gastrointestinal side effects

Info

Publication number: CN117677374A
Application number: CN202280050972.4A
Authority: CN
Inventors: 简斯蒂芬佩尔森·格鲁登; 安德斯·福斯伦德; 乌尔夫·郝拉姆巴克; 扬·阿维德·索德尔豪尔; 格兰·奥德布恩
Original assignee: Empros Pharma AB
Current assignee: Empros Pharma AB
Priority date: 2021-05-21
Filing date: 2022-05-20
Publication date: 2024-03-08

Abstract

The present invention relates to a composition of orlistat and acarbose for improving quality of life. The combination is administered orally to achieve a synergistic effect. The synergistic effect is obtained after a period of time of 13 weeks or more, for example, after a period of 14 weeks or more, after a period of 15 weeks or more, after a period of 16 weeks or more, after a period of 17 weeks or more, after a period of 18 weeks or more, after a period of 19 weeks or more, after a period of 20 weeks or more, after a period of 21 weeks or more, after a period of 22 weeks or more, after a period of 23 weeks or more, after a period of 24 weeks or more, after a period of 25 weeks or more, and after a period of 26 weeks or more. The synergistic effect improves the weight loss effect.

Description

Synergistic effect of orlistat and acarbose combination on weight loss, quality of life and reduction of gastrointestinal side effects

Technical Field

The present invention relates to the medical use of a combination of orlistat and acarbose to obtain a synergistic effect with respect to weight loss and reduction of gastrointestinal side effects. The invention also relates to the use of such a composition for obtaining an improved quality of life compared to baseline or placebo. The medical use is for weight loss, i.e. in situations where weight loss is desired, but it can be seen from the examples herein that the quality of life is significantly improved. The compositions of the invention are useful for the treatment of overweight and obesity; type 2 diabetes; elevated blood glucose levels (e.g., impaired glucose tolerance), polycystic ovary syndrome; lipoprotein metabolic disorders and other lipidemic conditions (such as hyperglyceridemia); non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis; metabolic syndrome; or weight loss prior to surgery. The composition may also be used for cosmetic purposes.

Background

It is estimated that 15 hundred million people are overweight and 5 hundred million people are obese worldwide. In general, more than one tenth of adults worldwide are obese. In 2010, over 4000 ten thousand children under five years of age were overweight. Overweight and obesity have been considered problems in high-income countries, but are now also on the rise in low-and medium-income countries, especially in urban environments. Overweight and obesity are the fifth greatest risk of death worldwide. At least 280 million adults worldwide die annually due to overweight or obesity. Furthermore, 44% of the diabetic burden, 23% of the ischemic heart disease burden, and 7% -41% of certain cancer burden can be attributed to overweight and obesity. The U.S. medical community officials approved obesity as a disease in month 6 of 2013.

Global concerns are great about this serious health problem, but different strategies have not been successful in reversing the obesity trend of the global population. Healthy diet and increased awareness of physical activity have also not proven particularly effective. There are several possible interpretations, for example: a healthy, affordable food or a safe place for sporting activities, especially in low-income blocks and communities; fresh foods suffer from disadvantages in terms of preservation, portability and palatability compared to snack or pre-packaged foods (pre-packaged foods); marketing of most unhealthy products by the food and beverage industry; and modern cultural habits increase sedentary behavior, decrease eating cadence and location (location), and lead to excessive stress and sleep insufficiency. Lifestyle interventions affecting dietary intake and energy expenditure are important, however, often insufficient. Obviously, obesity should be considered a chronic, incurable condition, requiring better pharmaceutical products for successful treatment. Thus, there is a need for a new, safe and effective medical procedure.

Type 2 diabetes mellitus is growing in popularity, which is closely related to obesity. Type 2 diabetes has a number of manifestations and suboptimal treatment (sub-optimal treatment) is associated with progressive beta cell failure. Although lifestyle measures (including eating habits and physical activities) should be first-line treatment measures (first-line treatment), it is difficult to succeed and almost always pharmaceutical intervention is required. Patients often have impaired glucose tolerance for a period of time before overt type 2 diabetes is diagnosed. If such impaired glucose tolerance, which may occur before or after weight gain, is properly treated, the progression to diabetes may be stopped or avoided. Current treatment options are limited to changing lifestyle, followed by metformin. Thus, there is a need for a new, safe and effective medical procedure.

Another indication of the invention is the treatment of overweight/obesity associated with polycystic ovary syndrome (Polycystic Ovary Syndrome, PCOS). Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, and this symptom occurs in 5% of women of childbearing age (conserved data). One of the most common direct symptoms is insulin resistance. Such insulin resistance is often associated with obesity, type 2 diabetes and high cholesterol levels. The current recommendations for the medical treatment (other than contraceptives) of obese and/or sugar-impaired polycystic ovary syndrome patients are limited to metformin, although current guidelines indicate that the evidence base is inadequate. The risk/benefit ratio of other insulin sensitizers (e.g., thiazolidinediones) is not ideal and therefore not recommended. For PCOS patients, there is a clinical need for a drug that can safely reduce body weight and improve glucose tolerance.

Nonalcoholic steatohepatitis (Nonalcoholic steatohepatitis, NASH) is liver inflammation and injury caused by fat accumulation in the liver. NASH affects 2% -5% of americans. Another 10% -20% of americans have fat in their liver, but no inflammation or liver injury, which is known as "fatty liver" or NAFLD. NASH and NAFLD are both becoming more and more common, probably because more and more americans are obese. At present, there is no specific therapy for NASH other than lifestyle intervention, and therefore there is an unmet clinical need.

According to the new definition of the international diabetes union (International Diabetes Federation, IDF), a person is defined as suffering from metabolic syndrome, who must have the following conditions:

central obesity (central obesity) plus any two of four factors:

elevated Triglyceride (TG) levels or specific treatments for such lipid abnormalities

High Density Lipoprotein (HDL) cholesterol lowering or specific treatment for such lipid disorders

Elevation of blood pressure or treatment of previously diagnosed hypertension

Elevated fasting blood glucose or previous diagnosis of type 2 diabetes

The inventors hypothesize that the proposed product will directly or indirectly affect most of the features (components) of metabolic syndrome, mainly weight loss, improved glycemic control, which in turn will lead to improved liver fat metabolism and lower triglyceride concentrations. The product is also expected to have a direct effect on triglyceride concentration.

Current treatment options for obesity and overweight

Some pharmacological principles have been considered for the treatment of obesity or overweight, including increasing energy expenditure (stimulants), inhibiting caloric intake (anorexics), limiting nutrient absorption, and regulating insulin production and/or action. Four centrally acting noradrenergic drugs (phentermine), diethylpropion (diethylpropion), trimethoprim (phendimetazine), benzphetamine (benzphetamine) are FDA approved for the treatment of obesity for generally less than 12 weeks. All of these are approved prior to determining the need for long-term treatment of obesity. Furthermore, there is no need to reach the current efficacy benchmark for weight loss (efficacy benchmarks) compared to placebo (average weight loss is 5% more than placebo group weight loss, or initial weight ratio of 5% less than placebo group weight loss is 35% or less, about twice the 5% ratio of placebo group weight loss). Drug averaging (on average) approved for long term weight management typically results in additional weight loss over placebo over a year ranging from about 3% (for orlistat and lorcaserin (lorcaserin)) to 9% (for phentermine/topiramate ER). As early as 2005, agonists including dinitrophenol, benzphetamine and ephedra were abandoned. Of the anorexic agents, sibutramine (sibutramine) is removed after several years of marketing due to adverse effects, and also the appetite suppressant Rimonabant (Rimonabant) of epiphyllum is removed together. Chlorine Carboxylic acid (loretin) is a selective serotonin 2C (5 HT 2C) receptor agonist, and is expected to reproduce the weight loss effect of fenfluramine without adversely affecting the heart. Lorcaserin moderately reduces body weight by about 3.2kg (about 3.2% of the initial body weight) more than placebo. In diabetics, lorcaserin treatment can reduce body weight and improve glycosylated hemoglobin concentration. LiraglutideLiraglutide injection) was approved (both EMA and FDA agency) as a therapeutic option for long term weight management in addition to low calorie diets and physical activity. The medicament is approved for adults with a Body Mass Index (BMI) of 30 or more (obese) or with a BMI of 27 or more (overweight) who suffer from at least one weight-related disorder, such as hypertension, type 2 diabetes or high cholesterol (dyslipidemia). GLP-1 analogues such as liraglutide and exenatide (exenatide) were originally used as type 2 diabetes drugs, but successful weight loss trials have been performed in which patients lost 8kg more weight than the placebo group one year after administration of the highest dose of liraglutide; the placebo group lost 2kg of body weight. However, these drugs have safety problems and mainly increase the risk of pancreatic cancer. The FDA still approves the use of liraglutide but encourages prescribers and patients to report possible side effects.

Over the last 20 years, about 10 different drugs have been put on the market, but have been withdrawn within a few years. Current alternatives include attempts to limit nutrient (lipid) absorption (orlistat), perhaps also using compounds that affect insulin (see below). In summary: the available drugs on a single unit basis with a positive benefit risk ratio for this patient population are very limited.

Currently, only orlistatAnd liraglutide->Is a globally available anti-obesity drug. Orlistat->Both strength (strength) of prescribed (120 mg) and over-the-counter (60 mg) drug were administered by the oral route. Orlistat is a semi-reversible local inhibitor of gastric and pancreatic lipases in the gastrointestinal tract and acts as an anti-obesity drug by preventing the intestinal tract from absorbing dietary fat (i.e. reducing energy intake). High lipophilic orlistat has a low absorbed dose fraction (log P8.5)<3 percent, thus the exposure of the plasma is lower<5 ng/ml). Orlistat is now provided in conventional relatively fast-release oral dosage forms. However, orlistat, while safe, also produces some side effects that severely hamper compliance. In clinical trials, more than about 25% of patients complain of gastrointestinal side effects, including diarrhea, oily spotting and fecal urgency (fecality). This, coupled with the insignificant (modest) effect on body weight (best case: 10% relative weight loss, placebo 6% relative weight loss), makes this conventional and relatively rapid release dosage form of orlistat unattractive to the vast majority of obese patients. However, the FDA clearly indicates in a recent report that orlistat is safe and has clinical benefit. Acarbose (acarbose) >Is a competitive alpha-glucosidase and pancreatic alpha-amylase inhibitor, which can inhibit the hydrolysis of oligosaccharides during gastrointestinal digestion. Acarbose has hydrophilicity (log P-8.1), so that acarbose has low intestinal permeability and low absorbed dose fraction<5%), low bioavailability and systemic exposure. Acarbose is available in conventional immediate release dosage forms and is currently used primarily in asia as a diabetes drug, but rarely in western countries. It has not been approved for the treatment of obesity.

Like orlistat, most patients using acarbose report problems of gastrointestinal tolerance (mainly bloating, diarrhea and gastrointestinal and abdominal pain), which limit their current clinical use in western countries.

There are two other α -glucosidase inhibitors currently on the market, miglitol (miglitol) and voglibose (voglibose). Miglitol is approved by the FDA and is sold in many countries, while voglibose is only approved in japan. Acarbose, miglitol and voglibose decrease HbA1c to about the same extent, but with slightly different side effects. Miglitol is 100% absorbed and excreted through the kidneys; whereas voglibose is similar to acarbose in that it is absorbed to a negligible extent. Voglibose is likely to be due to its low dose (0.2 mg voglibose per meal is a common dose), and its frequency of gastrointestinal side effects is lower compared to acarbose; but without reducing the gastric emptying rate. To date, studies have shown that all three α -glucosidase inhibitors are safe and have no systemic effects. Also a large number (> 1200 compounds) of the identified plant compounds show different alpha-glucosidase inhibitory effects. Acarbose stands out because it is the most clinically used and studied compound so far, is approved worldwide, and its patent has expired.

There is currently no other lipase inhibitor approved for the treatment of obesity, possibly other than cetiristat (cetilistat). Cetiristat has been shown to have similar weight loss effects as orlistat, but with much less frequent side effects. Cetiristat is currently only approved in japan. There are also some plant-derived lipase inhibitors, some of which are commercially available as over-the-counter drugs. Thus, the list of possible lipase inhibitors is very short.

From the above discussion, it can be seen that there is a need to develop compositions and dosing regimens for the treatment of obesity or overweight, which are compared to products currently on the market, in particularTablets are more effective than those of the prior art, and have reduced side effects and improved tolerability. The present invention is described in the patent application publication number WO 2016/097170 to the applicantDevelopment of the invention. It relates to modified release compositions of acarbose and orlistat which are present in three different fractions with different release patterns. Surprisingly, the results of a clinical study with this new composition for more than 6 months show that a synergistic effect of orlistat and acarbose is obtained, which means that the weight loss obtained with this new orlistat and acarbose composition treatment is increased compared to the effect expected based on the addition of orlistat and acarbose.

Disclosure of Invention

The present invention relates to a composition comprising orlistat and acarbose for improving the quality of life of obese or overweight individuals. The individual is a human. Typically, such compositions are used to treat obese or overweight individuals, and in addition to weight loss, the treatment results in an improvement in quality of life.

In general, obese or overweight individuals have a weight of 25kg/m ² The BMI above, e.g. 27kg/m ² 、29kg/m ² Above or 30kg/m ² The above. Overweight individuals have 25kg/m ² The above BMI, e.g. 25kg/m ² -less than 30kg/m ² And obese individuals have 30kg/m ² The above BMI.

The composition used according to the invention generally comprises orlistat and acarbose in a weight ratio of 2:1 to 4:1, for example 180/60, 150/50 or 120/40 orlistat/acarbose.

Improvement in quality of life is assessed by a questionnaire that includes questions in the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception. A suitable questionnaire commonly used in clinical trials is the RAND-36 health survey. Other suitable questionnaires are SF-36, weight impact on quality of life (IWQOL), obesity and weight loss quality of life (OWLQOL) or similar health surveys.

By questionnaire, the average overall health transition score can be measured. In general, an improvement in quality of life is observed when the average overall health transition is greater than 10 minutes, e.g., greater than 12 minutes, greater than 14 minutes, greater than 15 minutes, greater than 16 minutes, from baseline.

In general, the improvement relates to at least 5 of the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception. In particular, improvement is measured as an increase in physical function and/or overall health. The improvement in average score was increased by more than 10 compared to baseline.

The composition comprising orlistat and acarbose is administered once, twice or three times per day during the treatment period. Generally, the treatment period is 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. In particular, the treatment period is 26 weeks or more.

During the treatment period, the individual is asked to answer the questionnaire on a regular basis. The time interval for answering the questionnaire depends on the treatment period, but is typically at least 4 weeks, e.g. at least 6 weeks, at least 8 weeks or at least 26 weeks.

An improvement in quality of life is achieved regardless of the weight loss achieved by the individual during treatment. In particular, an improvement in quality of life and at least 5% weight loss of the individual during treatment is achieved.

Typically, the daily dose of orlistat during treatment is 30mg to 540mg or more, e.g. 30mg to 450mg or more such as 60mg to about 450mg or more, 90mg to about 450mg or more, about 120mg to 450mg or more, about 150mg to about 450mg or more, 180mg to 450mg or more such as 180mg to 450mg, 270mg to 450mg, 360mg to 450mg or more for adults.

Typically, the daily dose of acarbose during treatment is from 10mg to about 180mg or more, such as from 10mg to about 150mg, such as from 20mg to about 150mg, from 30mg to about 150mg, from 40mg to about 150mg, from 50mg to about 150mg, from 60mg to about 150mg or more, such as from 90mg to 150mg, 90mg or more, 120mg or more, or 150mg or more.

In embodiments, the composition comprises 90mg orlistat/30 mg acarbose, 120mg orlistat/40 mg orlistat, 150mg orlistat/50 mg acarbose or 180mg orlistat/60 mg acarbose.

Suitable compositions for use in accordance with the invention are designed for oral administration and are designed to release orlistat and acarbose at suitable locations in the gastrointestinal tract. To achieve this goal, suitable compositions may include granules (pellets), spheres (spheres), or pellets (pellets).

As described herein, suitable compositions are compositions in which orlistat is in micronized form (micronized form), i.e. having an average particle size of less than 50 μm, such as less than 20 μm, such as less than 10 μm. Furthermore, the inventors have found that orlistat and an enteric polymer may react in an undesired manner and thus, when the enteric polymer is present in the composition, the orlistat should be protected from direct contact with the enteric polymer. This can be achieved by using protective polymers, for example polymers selected from cellulose, cellulose derivatives and hydroxypropyl methylcellulose.

Specifically, the composition is an oral modified release composition comprising three or four different individual portions having different release patterns:

a) A first portion G1 comprising about 45% to about 65% by weight of the total dose of acarbose, for example about 50% to about 65%, about 55% to about 65% or about 60%,

b) A second portion G2A comprising about 35% to about 55% by weight, for example about 35% to about 50% by weight, about 35% to about 45% by weight or about 40% by weight,

c) A third portion G2B comprising about 50 wt% to about 85 wt%, such as about 55 wt% to about 80 wt%, about 60 wt% to about 80 wt%, about 65 wt% to about 75 wt%, about 68 wt% to about 75 wt%, about 72 wt% to about 73 wt%, such as about 72.2 wt%, of the total dose of orlistat, and

d) A fourth fraction G3 comprising about 15 wt% to about 50 wt%, such as about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 32 wt%, about 27 wt% to about 28 wt% or about 27.8 wt%,

the total concentration of acarbose and orlistat was 100 wt%,

wherein-when the composition comprises three parts, the three parts are i) G1, ii) G2, wherein G2A and G2B are combined, and iii) G3.

The design mode of the composition is as follows:

i) Part G1 is designed to release a fraction of the total acarbose dose in the stomach,

ii) the G2A moiety is designed to release a fraction of the total acarbose dose in the duodenum and jejunum; the release should be relatively quick, since acarbose should be able to exert its effect in the duodenum and jejunum,

iii) The G2B fraction is designed to release a fraction of the total dose of orlistat in the duodenum and jejunum; the release should be relatively fast, since orlistat should exert its effect in the duodenum and jejunum, and

iv) the G3 fraction is designed to release a fraction of the total dose of orlistat in the duodenum and jejunum.

b) Part c) and part c) may be combined into part G2.

The composition suitable for use according to the invention may be a composition wherein G1 is in the form of an inert core coated with a composition comprising acarbose, G2A and G2B are combined into G2, G2 is in the form of an inert core coated with a coating of acarbose and orlistat, then a coating with a protective polymer is provided, then coated with an enteric coating, G3 is in the form of uncoated granules.

The protective polymer is typically present in a concentration of at least 10 wt%, based on the total weight of G2, e.g. in the range of 10-20 wt%, 12-20 wt%, 13-20 wt%, 13.5-20 wt%.

The composition used according to the present invention may comprise modified-release particles, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80 based on the total weight of the modified-release particles, spheres or pellets. In embodiments, the G3 fraction comprises modified release granules, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80 based on the total weight of G3.

In general, the compositions used according to the invention have

i) The concentration of acarbose in the first part G1 ranges from 25% by weight to about 50% by weight, for example from about 30% by weight to about 45% by weight or about 40% by weight, based on the total weight of the G1 part, ii) the concentration of acarbose in the second part G2A or G2 ranges from about 0.5% by weight to about 4.5% by weight, for example from about 1% by weight to about 4% by weight, from about 1.5% by weight to about 3.5% by weight, from about 2% by weight to about 3.5% by weight, from about 2.5% by weight to about 3.25% by weight or about 3% by weight, based on the total weight of the G2A or G2, as appropriate,

iii) The concentration of orlistat in the G2B or G2 fraction ranges from 5% to about 30% by weight, e.g. from about 10% to about 25% by weight, from about 10% to about 20% by weight, from about 12% to about 20% by weight or about 15.5% by weight, based on the total weight of G2B or G2, as appropriate, and/or

iv) the concentration of orlistat in the G3 fraction ranges from 20 wt% to about 50 wt%, such as from about 25 wt% to about 50 wt%, from about 30 wt% to about 45 wt%, from about 35 wt% to about 45 wt%, or about 40 wt%, based on the total weight of G3.

As described above, the composition may include modified-release particles, spheres or pellets comprising from 35 to 60% by weight of cellulose or cellulose derivatives such as microcrystalline cellulose, based on the total weight of the modified-release particles, spheres or pellets.

In another aspect, the invention relates to the use of a composition comprising orlistat and acarbose for improving the quality of life of an obese or overweight individual. All details and specific comparisons of various aspects mentioned and described herein apply to this aspect.

Detailed Description

The present invention relates to a composition of orlistat and acarbose for use in medicine, wherein the composition is orally administered to obtain a synergistic effect with respect to weight loss and to obtain an improved quality of life compared to placebo, baseline or no treatment.

The clinical study reported herein gave the surprising result that treatment of obesity in obese individuals with a composition comprising orlistat and acarbose resulted in a significant improvement in the quality of life of the individuals. The clinical study used the accepted method RAND-36 to assess quality of life. RAND-36 is probably the most widely used health related quality of life (HRQoL) survey tool in the world today. It consists of 36 items, evaluating eight health concepts: physical function, role limitation due to physical health problems, role limitation due to emotional problems, social functions, emotional well-being, energy/fatigue, pain, and general health perception. The physical and mental health aggregate score (sum score) is also derived from the eight RAND-36 scales. RAND-36 is a set of quality of life metrics that are universal, consistent and easy to implement. These metrics rely on patient self-reporting and are now widely used by regulatory bodies for routine monitoring and assessment of adult patient care effects.

Overweight is defined herein as a BMI above 27 and obesity is defined herein as a BMI above 30. In this context, individuals with a BMI of 27 or more who have or are likely to have overweight-related diseases (e.g., diabetes, etc.) may require medical treatment to reduce or prevent such diseases by reducing body weight. However, it is contemplated that BMI of 27kg/m ² Above, e.g. 29kg/m ² Above or 30kg/m ² The above obese or overweight individuals will have a significantly improved quality of life when receiving overweight/obese treatment involving administration of a composition comprising orlistat and acarbose.

In general, improvement in quality of life is assessed by a questionnaire that includes questions in the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception. As described above, a suitable questionnaire is the RAND-36 health survey.

RAND-36 presents 36 problems. The answers to each question may be scored themselves, or the answers to each field may be scored. An average overall health transition score may also be obtained. The answers to the questions are compiled into eight-dimensional scores according to the standardized calculation program developed by RAND (RAND) corporation. This procedure allows comparison between different times and different populations. The procedure required:

1) It is checked whether the entered value is reasonable (e.g., if the response scale is 5 points, the value is between 1 and 5). Numbers outside the allowable range are set as missing,

2) Re-encoding the original data (including possible response table inversions) into calculated values (e.g., 1 to > 100),

3) Calculating scale points (scale points) for eight RAND domains

4) Explanatory text (labels) is provided for abbreviations of domain names (body functions, character functions/bodies, etc.).

As can be seen from the examples therein, the improvement in the average overall health transition score is 10 points or more, such as 12 points or more, 14 points or more, 15 points or more, 16 points or more, as compared to baseline.

If a placebo-controlled clinical study is conducted, the placebo score may or may not be compared.

In this context, the term "baseline" means the situation before starting the treatment with the composition comprising orlistat and acarbose, i.e. in terms of quality of life, the individual intended to receive the treatment with the composition comprising orlistat and acarbose has answered the questionnaire just before starting the treatment.

In general, improvements involve at least 5 of the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception.

Additionally or alternatively, the improvement in average score is increased by more than 10 as compared to baseline.

As described above, clinical studies conducted by the applicant have shown that acarbose and orlistat have a synergistic effect when administered orally simultaneously. The clinical study is described in detail in the experimental section herein. It is well known that oral administration of orlistat for 6 months results in a weight loss of about 2-3% after placebo adjustment. Notably, these studies were conducted in the censored population (vetted population) and combined with lifestyle guidelines. From literature it is inferred that oral administration of acarbose (at twice the dose used in the current trial) for 6 months resulted in a weight loss of about 0.5% after placebo adjustment. Thus, it is expected that oral administration of acarbose and orlistat will result in a placebo-adjusted weight loss of about 2.5% in the unexamined human population (non-vetted population). Surprisingly, an unexpectedly significant reduction in body weight was observed from the clinical results reported herein. Placebo-adjusted average relative weight loss was observed to be greater than 5% in the clinical study.

For therapeutic use herein, obesity is defined as a BMI of 30 or more. Overweight is defined as a BMI ranging from 25 to less than 30.

The invention results in a weight loss of at least 5%, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700% or more than 800% compared to placebo. The percentages are calculated as follows: 100% weight loss (kg) after treatment with the composition of the invention/weight loss (kg) after treatment with placebo (i.e. a composition without the active pharmaceutical substances acarbose and orlistat).

The synergistic effect reported in example 2 has been observed after 13 weeks of treatment and the effect increases further over a period of 13-26 weeks of treatment. It is contemplated that the synergistic effect is also effective over a longer treatment period, i.e., the synergistic effect is obtained after a period of time of 13 weeks or more of treatment, for example, after a period of time of 14 weeks or more, after a period of time of 15 weeks or more, after a period of time of 16 weeks or more, after a period of time of 17 weeks or more, after a period of time of 18 weeks or more, after a period of time of 19 weeks or more, after a period of time of 20 weeks or more, after a period of time of 21 weeks or more, after a period of time of 22 weeks or more, after a period of time of 23 weeks or more, after a period of time of 25 weeks or more, or after a period of 26 weeks or more.

The synergistic effect is obtained by orally administering orlistat and acarbose in a weight ratio of 2:1 to 4:1, for example in a weight ratio of 3:1.

Orlistat and acarbose should be administered simultaneously, preferably while eating. The administration may be once daily, twice daily or three times daily. The daily dosage of orlistat and acarbose depends on several individual factors (individual factors) such as the weight of the individual to be treated, risk-benefit analysis associated with side effects compared to the therapeutic effect. In general, the daily dosage of orlistat is 180mg to 450mg, such as 180mg to 450mg, 270mg to 450mg, 360mg to 450mg, and the daily dosage of acarbose is 60mg to about 150mg, such as 90mg to 150mg.

The composition used according to the invention may comprise 90mg orlistat/30 mg acarbose, 120mg orlistat/40 mg orlistat, 150mg orlistat/50 mg acarbose, 180mg orlistat/60 mg acarbose. The administration is typically carried out orally three times per day.

The daily dose of orlistat is 120mg for children aged 5-10 with a weight of 40-60kg, 270mg for children aged 5-10 with a weight of 60-70kg, and the same as for adults for children over 10 years and/or with a weight of over 70 kg.

The daily dosage of acarbose for children aged 5-10 with a weight of 40-60kg is 60mg, for children aged 5-10 with a weight of 60-70kg is 90mg, for children over 10 years and/or with a weight of over 70kg, the same as for adults.

For pediatric use, the dose should be taken 3 times daily, the dose being dependent on body weight; 40-60kg:60mg orlistat/20 mg acarbose, 60-70kg:90mg orlistat/30 mg acarbose, 70kg or more: adult dose.

Typically, the compositions of the present invention comprise 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. Herein, the term "modified release" is intended to mean that the release of the active pharmaceutical substance is manipulated by, for example, pharmaceutically acceptable excipients and/or coating materials; examples of coating materials that result in modified release are, for example, enteric coating materials; which may be selected to release the active drug substance at a pH above a specific value, e.g. a pH above the pH in the stomach; examples of pharmaceutically acceptable excipients that may lead to delayed release are, for example, cellulose or cellulose derivatives such as hydroxypropyl methylcellulose. Another way to obtain a modified release may be to use the water-soluble properties and/or pH-dependent solubility of the drug substance itself.

As mentioned above, the present invention is based on the invention as described in WO 2016/097170 by the applicant. However, in order to achieve the desired in vivo release, the composition must be modified. Surprisingly, this modification results in a synergistic effect of the two drug substances. This is a very important finding, since it means that weight loss can be achieved more quickly and efficiently, and that the desired weight loss can be achieved in a shorter time.

The compositions of the present invention include granules, spheres or pellets. Certain portions of the composition are designed to avoid release of the active substance in the stomach (e.g., by coating of the particles, spheres, or pellets, or by incorporating excipients with pH dependent release into the particles, spheres, or pellets).

Compositions comprising three or four different parts, each part having a defined in vitro release profile, are described in WO 2016/097170. However, the release rate of each fraction was based on simulation and in vitro studies. The composition used according to the invention also comprises three or four parts, G1, G2A, G B and G3; if it contains only three parts, then G2A and G2B are G2 parts.

The following focuses on the combination of orlistat and acarbose.

The release rate of the API is designed such that acarbose is released in certain parts of the stomach and small intestine by well-defined different formulation principles, while orlistat is released in the whole small intestine up to the jejunum end, but at different release rates. By releasing unchanged API at different rates, adequate inhibition of digestive enzymes is achieved; such that relevant amounts of undigested carbohydrates and lipids can reach the distal region of the small intestine. Digestive metabolites (fatty acids, monoacylglycerols and hexoses) formed locally by local digestion will then act as ligands stimulating the so-called gastrointestinal brake effect (gastro-intestinal brake effect).

Herein, the term RR means rapid release, DR means delayed release, and PR means prolonged release. Delayed release means that the release has been delayed, but may be very rapid or prolonged when the release is initiated. Subscript DC indicates a delayed coating, gasric indicates a start of release in the stomach, but drug substance may still be released after entering and passing through the small intestine up to the end of the jejunum, EC indicates an enteric coating, i.e. a coating of certain polymers having a pH cut off value of about 4, i.e. they do not dissolve at an acidic pH, and gradually start to dissolve at a pH of about 4. Polymers having pKa values of about 5.5 may be used, i.e. they begin to dissolve at a pH of about 5.5. Thus, since the drug substance is not released at a pH of less than 4, PROX-SI indicates that release should begin and occur primarily in the proximal small intestine, while INTESTINAL indicates that release should occur in the first portion of the small intestine up to the jejunum distal.

The present invention provides an oral drug modified-release (MR) composition designed to:

i) Releasing a portion of the total acarbose dose in the stomach, but in a delayed manner, to ensure that the acarbose-containing particles are thoroughly mixed with the food ingredients and chyme in the postprandial stomach,

ii) releasing a fraction of the total acarbose dose and a fraction of the total orlistat dose in the duodenum and jejunum; this release should be relatively fast, since both acarbose and orlistat can act in the duodenum and jejunum, and

iii) A fraction of the total dose of orlistat is released in the duodenum and jejunum.

As described above, various formulation principles may be used in accordance with the present invention to prepare compositions for use. Such formulation principles can be seen from the reference WO 2016/097170. However, in order to obtain a synergistic effect, the present inventors developed a composition comprising acarbose and orlistat, wherein the composition comprises different individual moieties. The composition may comprise three or four different moieties:

d) A fourth fraction G3 comprising about 15 to about 50 wt%, such as about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 32 wt%, about 27 wt% to about 28 wt% or about 27.8 wt%, of the total dose of orlistat, the total concentration of acarbose and orlistat being 100 wt%, respectively;

if the composition comprises only three parts, then part b) and part c) are combined. The combined fractions are designated G2. The release patterns of the different parts are different, as the parts are designed to release acarbose and orlistat in different parts of the gastrointestinal tract.

Furthermore, to obtain the desired in vivo release, the concentration of acarbose in the first part G1 ranges from 25 wt% to about 50 wt%, such as from about 30 wt% to about 45 wt% or about 40 wt%, based on the total weight of the G1 part. The concentration of acarbose in the second part G2A or G2 ranges from about 0.5% to about 4.5% by weight, for example from about 1% to about 4% by weight, from about 1.5% to about 3.5% by weight, from about 2% to about 3.5% by weight, from about 2.5% to about 3.25% by weight or about 3% by weight, based on the total weight of G2A or G2, as appropriate. The concentration of orlistat in the second part G2B or G2 ranges from 5 wt% to about 30 wt%, such as from about 10 wt% to about 25 wt%, from about 10 wt% to about 20 wt%, from about 12 wt% to about 20 wt%, or about 15.5 wt%, based on the total weight of G2B or G2, as appropriate. The concentration of orlistat in the third (or fourth) part G3 ranges from about 20 wt% to about 50 wt%, such as about 25 wt% to about 50 wt%, about 30 wt% to about 45 wt%, about 35 wt% to about 45 wt%, or about 40 wt%, based on the total weight of G3.

In order to obtain the desired in vivo release of the active substance, it is important to select pharmaceutically acceptable excipients that control the release of the active substance. In particular, the inventors focused on (addressed) partial release of orlistat from G2 (G2A, G2B) and G3 to obtain the desired in vivo release. The inventors have found that the enteric polymer contained in G2 may have a negative effect on the in vivo release of orlistat (and/or acarbose) from G2 (G2A, G B). The results indicate that by minimizing direct contact between the drug and the enteric polymer, the desired in vivo release can be achieved. When G2 (G2A, G2B) is in the form of granules, pellets or micropellets, by coating the granules, pellets and micropellets with a protective layer (prior to mixing or coating with an enteric polymer), direct contact between the drug substance and the enteric polymer can be minimized. It was found that the protective layer should have a certain thickness to ensure that the active substance in the G2 particles is not in direct contact with the enteric polymer. The thickness is expressed as the concentration of the protective layer in the final G2 (G2A, G2B) portion and its concentration should be at least 10 wt%, based on the weight of G2 (G2B, G2A), e.g. a concentration in the range of 10-20 wt%, 12-20 wt%, 13-20 wt%, 13.5-20 wt%.

Another observation is that a correct balance is obtained between the active substance and pharmaceutically acceptable excipients that confer G2B or G2 and/or G3 moiety modified release characteristics to obtain the desired in vivo release. Furthermore, in vivo release can be optimized by using orlistat in micronized form. Orlistat has very poor water solubility (less than 0.001 g/ml) and the use of micronized form of orlistat increases the surface area and thus the water solubility (rate of water solubility). Furthermore, the use of surfactants to mitigate contact between orlistat and fluids in the gastrointestinal tract has a positive impact on the in vivo release rate.

The G3 portion of the composition is intended to release orlistat in a delayed manner such that the orlistat is effective in the proximal intestine. To achieve this, orlistat is used in micronized form and the concentration of orlistat in this fraction should be much smaller than originally envisaged in WO 2016/097170.

Thus, the composition according to the invention comprises a G3 moiety comprising modified-release particles, spheres or pellets comprising orlistat, wherein the modified-release particles, spheres or pellets comprise 30-50 wt% micronized orlistat based on the total weight of G3. The modified release particles, spheres or pellets comprise orlistat.

Furthermore, the granules, spheres or pellets of G3 comprise 35-60 wt.% cellulose or cellulose derivatives such as microcrystalline cellulose.

Thus, in one aspect of the invention, the composition according to any of the preceding aspects comprises modified release particles, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80.

The invention also provides a composition as described herein, for example the composition described above.

Formulation of part G1, part G2 and part G3 of the composition

The G1 portion of the composition is designed to release acarbose in an extended manner. Prolonged release is achieved by providing a G1 moiety comprising acarbose and a prolonged release polymer or lipid. The extended release polymer typically has poor water solubility, i.e., it is a hydrophobic polymer, and may be selected from: ethylcellulose, acrylate or acrylic acid derivatives, gelatin, a coating agent selected from the group consisting of: based on polymethacrylic acid and methacrylate, copolymers of ethyl acrylate and methyl acrylate, acrylate and methacrylate copolymers, hydroxypropyl methylcellulose phthalate, 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, acetylated hydrogenated soybean oil glycerides, castor oil, preferably solid at room temperature, most preferably hydrogenated vegetable oils.

The hydrophobic polymer or lipid is typically present in G1 at a concentration of about 10% to about 50% by weight, such as about 15% to about 45% by weight, about 20% to about 40% by weight, about 15% to about 25% by weight, of the total weight of G1.

The hydrophobic polymer or lipid may be replaced or supplemented by hydroxypropyl methylcellulose or waxes, such as glyceryl monostearate, white wax, carnauba wax, stearyl alcohol, stearic acid, polyethylene glycol and triglycerides or mixtures thereof.

The hydroxypropyl methylcellulose or wax is typically present in the G1 at a concentration of about 3 wt% to about 50 wt%, such as about 3 wt% to about 45 wt%, about 3 wt% to about 40 wt%, about 3 wt% to about 35 wt%, about 3 wt% to about 30 wt%, about 3 wt% to about 25 wt%, about 4 wt% to about 20 wt%, about 4 wt% to about 15 wt%, about 4.5 wt% to about 10 wt%, or about 5 wt% to about 9.5 wt%, based on the total weight of the G1. In some cases, the concentration ranges from about 10% to about 50% by weight, such as from about 15% to about 45% by weight or from about 20% to about 40% by weight, of the total weight of G1.

Furthermore, to obtain the desired release in vivo, the concentration of acarbose in the first part G1 ranges from 25 wt% to about 50 wt%, e.g. from about 30 wt% to about 45 wt% or about 40 wt%, based on the total weight of the G1 part.

As can be seen from the examples herein, G1 can be prepared based on a neutral core, for example, by coating a microcrystalline cellulose core with a coating composition comprising acarbose.

The G2 portion of the composition is designed to have delayed release of acarbose and orlistat but is relatively rapid once release is initiated. This mode of release is obtained by combining the drug substance with one or more surfactants (in particular in order to increase the solubility of orlistat) and an enteric polymer (i.e. a polymer with pH-dependent solubility such that it is insoluble at low pH (typically at pH 4 or lower), but soluble at neutral/alkaline pH). The polymer may be incorporated into the G2 formulation or may be used as a coating material to encapsulate the G2 formulation. As previously mentioned, it is necessary to minimize any direct contact between the drug and the enteric polymer. This can be achieved by providing the spheres, particles or pellets containing the active pharmaceutical substance with a protective coating. Suitable polymers for use as protective polymers include cellulose or cellulose derivatives, such as hydroxypropyl methylcellulose or other film forming polymers.

Furthermore, orlistat must be used in micronized form in order to achieve the desired in vivo release. Therefore, the average particle size of orlistat should be 50 μm or less, for example 20 μm or less, 10 μm or less or 5 μm or less.

The surfactant is typically selected from the group consisting of anionic, cationic or nonionic surfactants. Nonionic surfactants such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitol monoisostearate, sorbitol monolaurate, sorbitol monopalmitate, sorbitol monostearate, sorbitol monooleate, sorbitol sesquioleate, sorbitol trioleate, glycerol monooleate and polyvinyl alcohol. Anionic surfactants include docusate sodium and sodium dodecyl sulfate. Cationic surfactants include, for example, benzalkonium chloride, benzethonium chloride, and cetrimide (cetrimide).

The total concentration of surfactants is typically present in G2 at a concentration of about 0.5% to about 30% by weight of the total weight of G2. Preferably, the concentration is from about 1 wt% to about 10 wt%, such as from about 1 wt% to about 8 wt%, from about 1 wt% to about 5 wt%, 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 methacrylate, ethyl acrylate and methyl acrylate, acrylate and methacrylate copolymers, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinyl acetate phthalate or mixtures thereof, for example, can be obtained from the company Shin-Etsu and Sitec under the trade name Sippic (hypromellose acetate succinate) is commercially available.

The enteric polymer is typically an acrylate or acrylic polymer or copolymer. The acrylic polymer may comprise one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylates and methacrylates having a low content of quaternary ammonium groups.

The acrylic polymer may be used in the form of an acrylic lacquer used in the form of an aqueous dispersion, such as may be obtained from Rohm pharmaceutical factory (Rohm Pharma) under the trade nameCommercially available or available from Colorcon under the trade name Acryl +.>Are commercially available. The acrylic coating may comprise a mixture of two acrylic paints, each of which is available under the trade name +.>30D and->30D is commercially available. />30D30D is a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth) acrylic acid esters being +.>30D is 1:20, in +.>30D is 1:40.

The mixture is insoluble in water and digestive juice. However, the coatings formed therefrom are swellable and permeable in aqueous and digestive fluids. / >The dispersions may be mixed together in any desired ratio to ultimately obtain a modified release formulation having the desired dissolution profile (dissolution profile).

In the G2 portion, the enteric polymer is typically present at a concentration of about 15% to about 50% by weight based on the total weight of the G2 formulation. Preferably, the concentration is from about 20 wt% to about 40 wt%, such as from about 15 wt% to about 40 wt%, from about 15 wt% to about 35 wt%, from about 15 wt% to about 30 wt%, from about 20 to about 25 wt%, based on the total weight of G2.

G2 The concentration of the protective polymer in the (G2A, G2B) moiety should be at least 10 wt%, e.g. in the range of 10-20 wt%, 12-20 wt%, 13-20 wt%, 13.5-20 wt%, based on the total weight of G2 (G2A and G2B).

The concentration of acarbose in the second part G2A or G2 ranges from about 0.5% to about 4.5% by weight, for example from about 1% to about 4% by weight, from about 1.5% to about 3.5% by weight, from about 2% to about 3.5% by weight, from about 2.5% to about 3.25% by weight or about 3% by weight, based on the total weight of G2A or G2, as appropriate. The concentration of orlistat in the second part G2B or G2 ranges from 5 wt% to about 30 wt%, such as from about 10 wt% to about 25 wt%, from about 10 wt% to about 20 wt%, from about 12 wt% to about 20 wt%, or about 15.5 wt%, based on the total weight of G2B or G2, as appropriate.

The G3 moiety is designed to release orlistat in an extended manner. Orlistat may have been released to a lesser extent (degree) in the stomach. Orlistat is very poorly water soluble and is combined with one or more surfactants in order to achieve the desired release. The surfactant may be one or more of those mentioned above under G2. The surfactant is present in G3 at a concentration of about 1% to about 30% by weight of the total weight of the G3 formulation. Preferably, it is present from about 2% to about 20%, from about 3% to about 20%, from about 5% to about 20%, from about 10% to about 15% by weight.

Alternatively or additionally, the release of orlistat from G3 can be obtained by incorporating water soluble or water swellable polymers such as hydroxypropyl methylcellulose or other cellulose derivatives such as methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, etc.

Such water-soluble polymers are typically incorporated into G3 formulations at a concentration of about 35 wt% to about 60 wt%, such as about 35 wt% to about 55 wt%, about 35 wt% to about 50 wt%, about 40 wt% to about 50 wt%, based on the total weight of G3. In some cases, the concentration may be about 70 wt% to about 90 wt% based on the total weight of G3. Preferably, the concentration is from about 40 wt% to about 50 wt%.

The concentration of orlistat in the third (or fourth) part G3 ranges from about 20 to about 50 weight percent, such as about 25 to about 50 weight percent, about 30 to about 45 weight percent, about 35 to about 45 weight percent, or about 40 weight percent, based on the total weight of G3.

The G1, G2 (or G2A, G2B) and G3 moieties may also comprise other pharmaceutically acceptable ingredients selected from those described herein. Furthermore, to prepare the final composition, G1, G2 (or G2A, G B) and/or G3 may be mixed with one or more pharmaceutically acceptable excipients, or G1, G2, and/or G3 may be coated with a film coating or coating that, for example, retards or reduces the negative impact of one part on another.

The G1 moiety of the composition may be in the form of granules, spheres, pellets, tablets, or the like, or the G1 moiety may be incorporated into a two-layer tablet wherein the G1 moiety is contained in one of the two layers. The layer comprising the G1 moiety may be provided with a delayed release coating.

The G2, or G2A and G2B portions of the composition may be in the form of granules, spheres, pellets, tablets, etc. containing an enteric polymer or having an enteric coating, or G2A and G2B are incorporated into a two layer tablet wherein the G2, or G2A and G2 portions are contained in one of the two layers and the layer containing the G2, or G2A and G2B portions has an enteric coating.

The G3 moiety may be in the form of a particle, sphere, pellet, tablet, etc., or it may be contained in a two-layer tablet, wherein the G3 moiety is contained in one of the two layers.

The final modified release composition according to the present invention may be in the form of a multi-unit tablet, a bilayer multi-unit tablet, a coated tablet, a multi-unit capsule or a multi-unit oral powder. In general, 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 multi-unit tablet, capsule, sachet (sachets) or powder.

In a preferred aspect, G1 is in the form of an inert core coated with a composition comprising acarbose; g2 is in the form of an inert core coating over which the drug substance is coated, then provided with a protective coating, then with an enteric coating. G3 is in the form of uncoated granules.

Other pharmaceutically acceptable excipients may be included in the G1, G2 or G3 formulations.

However, it should be understood that a synergistic effect should also be obtained by administering two compositions, one containing acarbose and the other containing orlistat, wherein the acarbose composition comprises a G1 moiety and a G2A moiety and the orlistat composition comprises a G2B moiety and a G3 moiety. To achieve a synergistic effect, the compositions should be administered to the individual simultaneously.

The compositions according to the invention comprise a G1 moiety, a G2 (or G2A and G2B) moiety and a G3 moiety, and optionally, one or more pharmaceutically acceptable excipients. Such compositions comprise 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80 based on the total weight of the composition.

Compositions of the invention

The invention also provides a composition comprising two or more parts having different release patterns. These parts are denoted G2 or G2B and G3. The composition comprises

i) A G2B moiety comprising about 50 wt% to about 85 wt%, such as about 55 wt% to about 80 wt%, about 60 wt% to about 80 wt%, about 65 wt% to about 75 wt%, about 68 wt% to about 75 wt%, about 72 wt% to about 73 wt%, such as about 72.2 wt%, of the total dose of orlistat, and

ii) a G3 fraction comprising about 15 to about 50 wt%, such as about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 32 wt%, about 27 wt% to about 28 wt% or about 27.8 wt%, of the total dose of orlistat, the total concentration of acarbose and orlistat being 100 wt%, respectively,

Wherein orlistat is present in the fraction in the form of micronized orlistat.

More specifically, the concentration of orlistat in the G2B fraction ranges from 5 wt% to about 30 wt%, such as from about 10 wt% to about 25 wt%, from about 10 wt% to about 20 wt%, from about 12 wt% to about 20 wt%, or about 15.5 wt%, based on the total weight of G2B. The concentration of orlistat in part G3 ranges from about 20% to about 50% by weight, e.g., from about 25% to about 50% by weight, from about 30% to about 45% by weight, from about 35% to about 45% by weight, or about 40% by weight, based on the total weight of G3.

The composition may also comprise G1 moieties and G2A moieties as described herein, and the G2A moieties and G2B moieties may be mixed to form G2 moieties.

All details given herein regarding part G1, part G2/(G2A/G2B) and part G3 apply mutatis mutandis to the above composition.

The invention also provides a composition comprising three or four different moieties:

a) A first portion G1 comprising about 45% to about 65% by weight of the total dose of acarbose, for example about 50% to about 65% by weight, about 55% to about 65% by weight or about 60% by weight,

b) A second portion G2A comprising about 35% to about 55% by weight, such as about 35% to about 50% by weight, about 35% to about 45% by weight or about 40% by weight,

c) A third portion G2B comprising about 50 wt% to about 85 wt%, such as about 55 wt% to about 80 wt%, about 60 wt% to about 80 wt%, about 65 wt% to about 75 wt%, about 68 wt% to about 75 wt%, about 72 wt% to about 73 wt%, such as about 72.2 wt%, and

d) A fourth fraction G3 comprising about 15 wt% to about 50 wt%, such as about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 32 wt%, about 27 wt% to about 28 wt% or about 27.8 wt% of the total dose of orlistat, the total concentration of acarbose and orlistat being 100 wt%, respectively;

if the composition comprises only three parts, then part b) and part c) are combined. The combined fraction is called G2. The release patterns of the different parts are different, as the parts are designed to release acarbose and orlistat in different parts of the gastrointestinal tract.

All details given herein regarding part G1, part G2 (G2A/G2B) and part G3 apply mutatis mutandis to the above composition.

Orlistat (tetrahydro Li Pu statin)

Chemical structure of orlistat ((S) -1- ((2S, 3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) 2-carboxamido-4-methylpentanoate):

orlistat can be prepared from biological material (streptomyces toxinus (Streptomyces toxytricin)) or can be synthetically or semisynthetically prepared.

According to the literature, orlistat occurs in two different crystalline forms, form I and form II. The melting points of form I and form II were 44℃and 43℃respectively. The Roche company (Roche) sells in Sweden under the nameThe product of the capsule contains form II. Orlistat appears to be absent in the form of a salt. It is hardly soluble in water。

In this context, the term "orlistat" covers the chemical structures described above and any optical isomers thereof, as well as any crystalline forms, any polymorphs, any hydrates, any pharmaceutically acceptable or any prodrugs thereof.

Orlistat is a topical inhibitor of gastric and pancreatic lipase in the gastrointestinal tract, preventing the absorption of dietary fat by the gut by inhibiting endoluminal digestion (luminal digestion). The physicochemical conditions in the stomach and small intestine are very dynamic, and this activity will be significantly different from the kinetics of orlistat inhibition. The design of such fixed oral MR dosage forms takes into account these dynamic gastrointestinal conditions. Conventional dosage forms The ratio of the oral absorbed doses of orlistat is lower<3 percent, thus the exposure of the plasma is lower<5 ng/ml). However, orlistat, while safe, has side effects that severely hamper compliance. In clinical trials, more than about 25% of patients complain of gastrointestinal side effects, including diarrhea, oily spotting and urgency. In addition, the effect on body weight is not great, so that +.>The appeal to the vast majority of obese patients is reduced. However, FDA explicitly indicates +.>Is safe and has clinical benefit. Clinical use of oral Modified Release (MR) dosage forms of orlistat not only reduces fat gastrointestinal absorption by preventing the breakdown of triglycerides into free fatty acids and monoacylglycerols; orlistat also alters gastrointestinal transit time and affects satiety by many of the cell types mentioned above and below. />

In the stomach, decreased lipid digestion by orlistat increases gastric emptying (faster delivery of food to the duodenum). If the dietary fat content is high, diarrhea may occur within 30 minutes after a meal. This diarrhea is most likely due to the food in the stomach which normally causes the colon to empty. This signal, coupled with the excessive amount of fat in the stool of the previous meals (resulting in reduced absorption of water during colonic transit), may lead to diarrhea. A high fat diet may further enhance gastric to colonic signals, thereby exacerbating the situation. Since fatty acids, but not intact triglycerides, are ligands for gastrointestinal receptors, many of the above hormones will be secreted at lower levels when lipid digestion that normally occurs in the stomach is inhibited. Notably, are:

1) In the duodenum, the fatty acid signal of CCK is weakened and bile secretion is reduced, thereby further reducing fat digestion.

2) The loss of the appetite stimulating hormone ghrelin (ghrelin) caused by a normal diet is reduced.

3) L cells (which secrete incretins) also secrete less GLP-1, resulting in less ileal braking.

Undigested triglycerides enter the colon, and as mentioned above, fat only enters the colon in small amounts. A large amount of fat will result in a faster rate of advancement through the colon and less water is absorbed. In summary, the current way of delivering orlistat in conventional dosage forms, including drug release in the stomach, to the gastrointestinal tract, on the one hand, removes calories in the form of intact undigested triglycerides, but on the other hand causes many side effects, bypasses many appetite regulating systems in the gastrointestinal tract, and also increases the gastric emptying rate, which in effect reduces satiety and increases appetite.

Acarbose candy

Acarbose (chemical structure of O-4, 6-dideoxy-4- [ [ (1 s,4r,5s,6 s) -4,5, 6-trihydroxy-3- (hydroxymethyl) cyclohex-2-enyl ] amino ] - α -D-glucopyranosyl- (1→4) -O- α -D-glucopyranosyl- (1→4) -D-glucopyranose:

Acarbose may be prepared from biological material (Actinoplanes) or may be prepared synthetically or semisynthetically.

No information is found in the literature about the acarbose crystalline form. However, some data indicate that acarbose may be amorphous and that acarbose does not appear to exist in salt form. It is very soluble in water according to the european pharmacopoeia (ph.eur.).

Herein, the term "acarbose" encompasses the chemical structures described above and any optical isomers thereof, as well as any crystalline forms, any polymorphs, any hydrates, any pharmaceutically acceptable or any prodrugs thereof.

Acarbose candyIs a competitive alpha-glucosidase and pancreatic alpha-amylase inhibitor, which can inhibit oligosaccharide hydrolysis during the gastrointestinal digestion process of the diet. Acarbose is currently used mainly in asia as a diabetes drug, but is rarely used in western countries. By inhibiting lumen digestion and subsequent absorption of carbohydrates, the glucose concentration in postprandial blood glucose increases slower and patient demand for insulin decreases. The low intestinal permeability of acarbose (due to its hydrophilic nature) results in less than 5% of the drug being absorbed after oral administration. Low GI absorption and bioavailability results in very low plasma exposure, which makes acarbose considered a safe drug without systemic side effects. Like orlistat, most patients with acarbose report gastrointestinal tolerability problems (mainly flatulence, diarrhea and gastrointestinal and abdominal pain), which limit their current clinical use in western countries. The severity of gastrointestinal side effects is directly related to the intensity of the oral dose, in a stepwise fashion. Furthermore, the side effects of acarbose appear to be "diet driven". In asian countries, higher carbohydrate intake and possibly slightly higher "resistant" carbohydrate intake (slower digestion rate) appear to reduce the rate of side effects. In addition, patients were advised to slowly introduce acarbose over 1-3 weeks, with 50mg daily, and then slowly increase the oral dose to up to 100mg per meal. As more undigested carbohydrates enter deep in the gastrointestinal tract, more local production occurs in the distal small intestine Many enzymes treat undigested carbohydrates. Although acarbose can also remove ligands of various cell types throughout the gastrointestinal tract, some notable differences are observed. Acarbose will reduce gastric emptying rate, probably by delivering less ligand to the K cells secreting GIP in the proximal small intestine and more ligand to the L cells secreting GLP-1 distally. Acarbose also causes more undigested polysaccharide to enter the proximal colon where bacteria ferment the polysaccharide, and the short chain fatty acids produced can bind to L cells to enhance ileal braking.

It should be understood that any of the features and/or aspects discussed above in connection with the compositions apply by analogy to the methods described herein.

The following examples of the drawings are provided to illustrate the invention. They are intended to be illustrative and should not be construed as limiting in any way.

Drawings

Fig. 1 shows details and results thereof concerning the clinical study described in example 2 herein.

Figure 2 shows the relative weight loss over a 26 week study, see example 2.

Figure 3 shows the proportion of participants who lost more than 5% and 10% of their body weight. More than 5% (p <0.0001 for both active treatment groups compared to placebo) and more than 10% (p <0.1 for both active treatment groups compared to placebo) of patients were reduced in the active treatment group at week 26.

Figure 4 shows the correlation between relative weight loss and change in RAND-36 project health transition (from baseline to week 26) in three groups.

Examples

Example 1-a composition comprising three parts G1, G2 and G3 was prepared:

the composition of the EMP16-02-60/20 modified release capsule containing 60 mg/unit orlistat and 20 mg/unit acarbose is as follows:

the composition of the EMP16-02-90/30 modified release capsule containing 90 mg/capsule orlistat and 30 mg/unit acarbose is as follows:

/>

the composition of the G1 granule containing 391.5mg/G acarbose is as follows:

^*) evaporation during manufacture

The composition of the G2 granules containing 155.8mg/G orlistat and 29.7mg/G acarbose is as follows:

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^*) evaporation during manufacture

The composition of the G3 particles containing 400.0mg/G orlistat was as follows:

^*) evaporation during manufacture

EXAMPLE 2 clinical Studies

A multicenter, double blind, placebo controlled, randomized study was conducted for twenty-six weeks in overweight and obese patients.

The main objective was to evaluate the effect of EMP16-02 (120 mg orlistat/40 mg acarbose and 150mg orlistat/50 mg acarbose) on relative weight loss compared to placebo after 26 weeks of oral treatment.

The secondary objectives are:

i) The effect of two different doses of EMP16-02 (120 mg orlistat (O)/40 mg acarbose (a) and 150mg O/50mg a) on relative and absolute weight loss compared to placebo during 26 weeks of oral treatment was evaluated;

ii) two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) were evaluated for their effect on other anthropometric features (anthropometric characteristic) compared to placebo during 26 weeks of oral treatment;

iii) The effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) on satiety and dietary pattern compared to placebo during 26 weeks of oral treatment was evaluated;

iv) two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) were evaluated for their effect on empty stomach insulin, glucose metabolism markers, lipid metabolism markers and inflammation markers compared to placebo during 26 weeks of oral treatment;

v) evaluation of the effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) on blood pressure compared to placebo during 26 weeks of oral treatment;

vi) assessing the effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) on quality of life compared to placebo during 26 weeks of oral treatment;

vii) evaluate the relationship between shedding (drop-out) and tolerability of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) compared to placebo during 26 weeks of oral treatment;

viii) two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) were evaluated for safety and Gastrointestinal (GI) tolerability compared to placebo during 26 weeks of oral treatment.

Exploratory goal:

the effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) on empty plasma/serum apolipoprotein A1 (ApoA 1) and apolipoprotein B (ApoB) levels during 26 weeks of oral treatment compared to placebo was evaluated.

Plasma levels of orlistat and acarbose at steady state prior to administration were assessed.

The effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) on relative and absolute weight loss compared to placebo after 6 months of oral treatment after completion of 26 weeks was evaluated.

The effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50 mgA) on HbA1c concentration compared to placebo after 6 months of oral treatment after completion of 26 weeks.

The effect of two different doses of EMP16-02 (120 mg O/40mg A and 150mg O/50 mgA) on blood pressure compared to placebo after 6 months after completion of 26 weeks of oral treatment was evaluated.

Diagnostic and primary qualification criteria

Overweight or obese male and female patients, defined as having a Body Mass Index (BMI) of 30 or 28kg/m2 in the presence of other risk factors such as hypertension, blood glucose disorders such as impaired glucose tolerance and glucose regulation disorders such as type 2 diabetes (T2 DM) and/or dyslipidemia.

Age 18 years less than or equal to age 75 years. Written informed consent to participate in the study is willing and able to be signed.

Body weight stabilization (changes reported <5% over 3 months prior to screening and randomization).

The primary endpoint was the% relative change from baseline in body weight compared to placebo after 26 weeks of treatment with EMP16-02 (120 mg O/40mg A).

A total of 156 patients participated in the study.

Patients were randomized to receive two doses of EMP16-02:

1.EMP16-02 120mg O/40mg A

2.EMP16-02 150mg O/50mg A

3. placebo (same capsule)

For EMP16-02 120/40, 2 capsules of EMP16-02 60/20 were used.

For EMP16-02 150/50, 1-grain EMP16-02 60/20 capsule and 1-grain EMP16-202 90/30 capsule were used.

Blood sampling (fasting) and anthropometric measurements were performed. The patient received electronic diary instructions and was asked to fill out a satiety and eating impulse (rating) questionnaire before breakfast (at the clinic) and then every hour for 4 hours until before the meal (at home). The clinic supplies standardized breakfast. At half the 2 nd visit breakfast, all patients received a placebo capsule, independent of the treatment group to which the patient was randomly assigned, providing the patient with the opportunity to self-administer IMP training under supervision of the clinic staff. The patient also receives instructions to fill out more questionnaires regarding health and quality of life, dietary patterns, activity and sleep, and gastrointestinal symptoms (gastrointestinal scoring scale [ GSRS ]).

The patient is instructed to take EMP16-02 or placebo every meal half way and about 100-200mL of water (or other beverage) on all subsequent treatment days. Once the IMP is dispensed, the patient is free to leave the clinic. The first randomized IMP dose was taken at home at lunch (or next meal).

Patients receiving EMP16-02 at random were dosed progressively higher starting with a run-in period of 6 weeks. Starting at week 7, all patients reached the final expected dose and began a 20 week treatment and observation period. The break-in period starts with a dose of three times daily (TID) of 60mg O and 20mg a, followed by a dose increase of 30mg O/10mg a every two weeks until the target doses of 120mg O/40mg ATID (low dose group) and 150mg O/50mg ATID (high dose group) are reached. The dosing regimen was as follows:

placebo treatment included matched oral capsules. Placebo and EMP16-02 capsules were TID taken with three meals daily.

Patients were sent to the clinic at visit 3 (week 7), visit 4 (week 14) and visit 5 (week 26) for safety assessment, and weight and anthropometric assessment. The patient arrived in the morning after a fasting of at least 8 hours overnight. All visits were initiated with a brief physical examination followed by blood drawing (fasting) and assessment of body weight and body composition. The patient provided standardized breakfast during the period of taking the IMP. All or part of the questionnaire, including satiety and dietary impulse, was filled in a manner similar to visit 2.

After 18 and 22 weeks of treatment (123±3 days and 151±3 days, respectively), the patient was asked to answer questions regarding IMP compliance, AE incidence, and concomitant medication (concomitant medication) use with an electronic diary.

The patient was issued a new IMP on visit 2, 3 and 4.

At visit 5 (week 26), the patient will take the last dose at the clinic when they eat breakfast. The 6 th visit is considered as a safe follow-up visit. The 7 th visit was a 6 month follow-up with one consent to patients who had completed 26 weeks of treatment with EMP16-02 (120 mg O/40mg A and 150mg O/50mg A) or placebo.

Duration of treatment

Each patient received 3 doses of EMP16 or matched placebo for 26 weeks per day. IMP is taken with 3 tons of main meal per day.

Efficacy assessment

Body weight, other anthropometric measures (BMI, waistline, sagittal diameter (sagittal diameter), bioimpedance), blood sampling of fasting lipid metabolism, glucose metabolism and inflammatory markers, blood pressure, questionnaires (dietary patterns, GSRS, satiety and dietary impulses, activity and sleep and health and quality of life [ RAND-36 ]), shedding rate (drop-out rate) (assessed in terms of both safety and effectiveness).

Diet patterns, satiety and eating impulses, and health and quality of life (RAND-36) questionnaires were analyzed using the Wilcoxon rank sum test. GSRS questionnaires were analyzed using ANCOVA, while activity and sleep questionnaires were analyzed using chi-square test. The shedding rate (overall and gastrointestinal correlation) after treatment with EMP16-120/40 or EMP16-150/50 was analyzed using the chi-square test versus placebo without continuity correction.

Summary of results

Efficacy results

Patients treated with EMP16 for 26 weeks significantly reduced body weight more than patients treated with placebo (p <0.0001 in both active treatment groups compared to placebo group at week 26). Average relative weight loss after 26 weeks of treatment with EMP16-120/40 or EMP16-150/50

-5.8% and-6.5% compared to-0.7% relief in placebo group after 26 weeks of treatment.

Average absolute weight loss in EMP16-120/40, EMP16-150/50 and placebo groups was-5.75 kg, -6.44kg and-0.78 kg, respectively. The same trend was also observed after 14 weeks of treatment and for women treated with EMP16-120/40 or EMP16-150/50 and men treated with EMP16-150/50 also after 14 and 26 weeks of treatment.

More patients in the 26 th week active treatment group had a weight loss of > 5% (p < 0.0001) and > 10% (p=0.0029 in EMP16-120/40 groups p=0.0029 and p=0.0034 in EMP16-150/50 groups p=0.0034) compared to placebo group. In general, 55% and 67% of patients in the EMP16-120/40 and EMP16-150/50 groups, respectively, lost more than or equal to 5% of their body weight between baseline and 26 th cycles, and 13% in the placebo group. 23% and 22% of the patients in the active treatment group lost more than or equal to 10% of their weight, while in the placebo group they lost 2.2%. The same trend was also observed after 14 weeks of treatment, as well as in women treated with either EMP16-120/40 or EMP16-150/50 at 14 and 26 weeks, but not in men treated with either dose.

BMI and waist circumference were significantly reduced in patients treated with EMP16 for 26 weeks compared to placebo (BMI: p for EMP16-120/40 compared to placebo<0.0001, waistline: p=0.0087; for EMP16-150/50, p=0.0047). The mean relative and mean absolute changes in BMI from baseline in EMP16-120/40 groups were-5.8% and-2.08 kg/m, respectively ² EMP16-150/50 group-6.5% and-2.23 kg/m ² Placebo group was-0.7% and-0.25 kg/m ² . Average absolute changes in waist circumference from baseline in EMP16-120/40 were-6.61 cm, -6.80cm and-3.36 cm respectively,

EMP16-150/50 group and placebo group at week 26, respectively. For BMI, the same trend was also observed after 14 weeks of treatment. At week 14, there was no statistically significant difference in waist circumference between the active and placebo groups.

Sagittal diameter and body composition (expressed as percent body fat) of patients treated with EMP16-150/50 for 26 weeks were significantly reduced compared to placebo-treated patients (sagittal diameter: p=0.0020, percent body fat: relative and absolute changes from baseline, p=0.0047 and p=0.0035, respectively). At week 26, the mean absolute change in sagittal diameter from baseline was-1.89 cm for EMP16-150/50 group and-0.49 cm for placebo group. The mean relative and mean absolute changes in percent body fat from baseline for EMP16-150/50 groups were-5.4% and-2.21, respectively, and for placebo groups were-0.3% and-0.19, respectively. There was no statistically significant difference in sagittal diameter and body composition between patients treated with EMP16-120/40 and placebo-treated patients at week 26. The same trend was also observed after 14 weeks of treatment, except that there was a statistically significant difference in sagittal diameter between the EMP16-120/40 group and placebo group.

In general, the active treatment group and placebo group did not differ significantly in satiety, dietary impulse and dietary pattern. During the course of the study, the appetite of patients in any of the treatment groups was not particularly affected, and most patients appeared to follow more or less the healthy diet habit advice at baseline. Overall, all treatment groups had slight and similar improvements in diet habits of vegetables and rhizome vegetables, fruits and berries, and fish and seafood. At week 26, the EMP16-150/50 group significantly improved the eating habits associated with desserts (biscuits, chocolate, candy, chips, soft drinks) and breakfast habits compared to the placebo group.

Over time, there was no clinically relevant change in fasting glucose metabolic markers (glucose, insulin, hbA1 c), albumin, or CRP from baseline for any of the treatment groups. Over time, the lipid metabolism markers low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol) and cholesterol but not triglycerides of the actively treated group decreased more than the placebo group. Although the differences compared to placebo were statistically significant at most time points of the analysis, small changes from baseline were not considered clinically relevant. Furthermore, apoA1 and ApoB in the actively treated group appeared to be more reduced compared to baseline than in the placebo group, but changes from baseline were not considered clinically relevant. Likewise, in any of the treatment groups, there was no clinically relevant change in liver enzymes (alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), alkaline phosphatase (ALP), or Gamma Glutamyl Transferase (GGT)) from baseline.

At any time point, there was no statistically significant difference between the active treatment group and the placebo group in terms of diabetes and pre-diabetic status. At baseline and week 26, the proportion of diabetics was 9.6% and 4.5% in the EMP16-120/40 group, 3.8% and 2.2% in the EMP16-150/50 group, and 9.6% and 13% in the placebo group, respectively. Whereas at the corresponding time points the proportion of pre-diabetic patients was 25% and 20% in the EMP16-120/40 group, 27% and 22% in the EMP16-150/50 group, and 37% and 22% in the placebo group, respectively.

Over time, there was no clinically relevant change in blood pressure from baseline for any of the treatment groups. The mean absolute change in systolic blood pressure from baseline ranged from-2.7 to-2.2 mmHg for the EMP-120/40 group, from-6.9 to-3.2 mmHg for the EMP-150/50 group, and from-2.2 to-1.8 mmHg for the placebo group. The mean absolute change in diastolic blood pressure from baseline ranged from-3.0 to-2.4 mmHg for EMP-120/40, from-3.3 to-1.0 mmHg for EMP-150/50, and from-1.5 to 0.7mmHg for placebo.

According to RAND-36 health surveys, the health-related quality of life of the active treatment group improved more than the placebo group during baseline and week 26. The physical function and overall health of both active treatment groups were significantly increased compared to placebo. Furthermore, the improvement in physical pain, energy/fatigue and emotional well-being was significantly higher in the patients of the EMP150/50 group than in the placebo group. The average overall health transition scores for the EMP-120/40 and EMP-150/50 groups increased by 18.5 and 16.5 points, respectively, significantly higher than the 5.9 points increased for the placebo group (p=0.0058 for the EMP16-120/40 group compared to the placebo group, p=0.0111 for the EMP150/50 group). There was no significant difference between the active treatment group and the placebo group in terms of changes in sleep patterns or heavy physical labor performance.

The overall shedding frequency between treatment groups was comparable; 15.4%, 13.5% and 11.5% of the patients in the EMP16-120/40, EMP16-150/50 and placebo groups, respectively, were discontinued prematurely.

The results are shown in FIGS. 1-4 and the following tables:

table 1: baseline characteristics of all randomized participants

The data are mean (SD) or n (%). In the EMP16 group 120/40, one participant was Asian, one was African Americans, and the rest was white. BMI = body mass index. Bp=blood pressure. Hba1c=glycosylated hemoglobin A1c. HDL = high density lipoprotein. LDL = low density lipoprotein.

Table 2: estimated change in body weight from baseline to week 14 and week 26

The mean data (SD) and estimated variance (95% confidence interval) of ITT analysis sets with LOCF interpolation (LOCF interpolation). ITT = intended treatment population, measured after each received at least one first dose. LOCF = last observed value inversion method. SD = standard deviation analyzed with ANCOVA and LCOF interpolated on missing data.

¹ Using Chi square (Chi) ² ) The percentage of the population with weight loss of 5% or more or 10% or more was analyzed and expressed as the participant ratio (%) and the ratio (odds ratio).

Unlike placebo, p<0.01

Unlike placebo, p<0.0001

Table 3: minor outcome variable, absolute change from baseline to week 26

The observed mean data (SD) and estimated variance (95% confidence interval) were analyzed using ITT analysis sets without interpolation. Covariance analysis was interpolated using last observed value transfer (LOCF). Changes during the test at weeks 7 and 14 are seen in the appendix.

Hba1c=glycosylated hemoglobin A1c. HDL = high density lipoprotein. ITT = intent to treat population. LDL = low density lipoprotein. LOCF = last observed value inversion method. Sd=standard deviation.

Table 4: questionnaire, absolute change from baseline to week 26

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The observed mean data (SD) and estimated variance (95% confidence interval) were analyzed using ITT analysis sets without interpolation. Covariance analysis was interpolated using last observed value transfer (LOCF). Changes during the test at weeks 7 and 14 are seen in the appendix. GSRS = gastrointestinal symptom rating scale, wherein a higher score indicates a higher intensity. RAND-36 = 36 short health surveys, where a higher score indicates a better quality of life. ITT = intent to treat population. Sd=standard deviation.

Table 5: more than or equal to 5% of the participants who reported in any group were withdrawn and had adverse events

The data are shown as number of participants (percentage of treatment group) and number of events. The data is from a safe population (safety population), i.e. all participants who received at least one therapeutic dose at random. AE = adverse event. MedDRA = supervision active medical dictionary. PT = preferred term.

Appendix table

Table A2: other baseline characteristics of all random participants (safety population)

ALT: alanine aminotransferase, AST: aspartate aminotransferase, ALP: alkaline phosphatase, GGT: gamma glutamyl transferase

Table A3: questionnaire, baseline data [ average Score (SD) ]

¹ Sum of five different satiety and eating impulse related problems

² Sum of seven problems related to meal patterns

³ Quality of life tool

⁴ Gastrointestinal symptom rating scale

Table A4: weight loss of the major outcome variable, i.e., the relative change from baseline to week 14 and week 26 in the Protocol-on-schedule (Per Protocol) population and post-hoc interpolation (post-hoc interpolation) population.

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The relative weight loss data is the average (SD) of observations using available data from pp=the population by protocol and phip=the population post interpolation. The number of participants in PP is: 41 (EMP 16-120/40), 41 (EMP 16-150/50) and 40 (placebo). The number of PHIP participants was: 48 (EMP 16-120/40), 50 (EMP 16-250/50) and 51 (placebo).

Representing a difference from placebo, p<0.0001

Table A5: the absolute changes in secondary outcome variables and vital signs were measured in humans from baseline to week 14.

Table A6: absolute change in minor outcome variable from baseline to week 7 and week 14 blood samples.

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The observed mean data (SD) is the ITT analysis set interpolated using LOCF. Treatment differences are expressed as estimated mean and 95% confidence interval. ¹ When fasting blood glucose is not less than 7.0mmol/L, the glucose tolerance state is defined as diabetes; when fasting blood glucose is between 6.1mmol/L and 7.0mmol/L, the glucose-tolerant state is defined as pre-diabetes and is expressed as n (%).

Table A7: secondary safety outcome variables, baseline values, and absolute changes at weeks 7, 14, and 26.

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Table A8: satiety and eating impulse-total score (mean ± standard deviation)

¹ Absolute change from baseline

Table A9: dietary pattern-total score (mean ± standard deviation). Higher scores indicate healthier meal patterns.

Visit to the doctor	EMP16 120mg/40mg		EMP16 150mg/50mg		Placebo
						Baseline-visit 2 (score)	9.5(2.3)		8.3(2.6)		9.1(2.5)
Week 7-visit 3 ¹	1.1(1.6)	0.6575	1.8(2.3)	0.3170	1.3(2.0)
						Week 14-4 visit ¹	1.3(1.9)	0.6813	1.6(2.3)	0.3568	1.0(1.8)
Week 26-visit 5 ¹	1.1(2.3)	0.9593	1.7(2.4)	0.2096	0.9(1.8)

¹ Absolute change from baseline

Table a10: diet pattern-how often you eat a biscuit, chocolate, candy, potato chip or soft drink (average ± standard deviation). Higher scores indicate less consumption.

Visit to	EMP16 120mg/40mg		EMP16 150mg/50mg		Placebo
						Baseline-visit 2 (score)	2.1±0.8		1.5±0.9		1.8±0.8
Week 7-visit 3 ¹	0.3±0.7	0.0529	0.8±1.0	0.4962	0.6±0.8
						Week 14-visit 4 1	0.3±0.8	0.2738	0.6±1.0	0.4371	0.5±0.8
Week 26-visit 5 ¹	0.3±0.7	0.9739	0.8±0.9	0.0086	0.3±0.8

¹ Absolute change from baseline

Table a11: meal pattern-how often you eat breakfast? (average mean.+ -. Standard deviation). Higher scores indicate more frequent breakfast consumption.

¹ Absolute change from baseline

Table a12: sleep and activity questionnaires

Percentage of participants who answer "yes" to the question posed. There was no significant difference between the active group and placebo (data not shown).

Table a13: adverse events listed by system organ category and preferred terminology (safety crowd)

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The AE, "back pain due to traffic accident", is encoded in multiple med dra terms and is denoted as a single AE in the table. n, number of individuals; m, the number of events. The percentages are based on the number of random individuals. Baseline events (events occurring prior to the first dose) were omitted from the summary.

Table a14: gastrointestinal tolerance at baseline (GSRS) and absolute changes after weeks 2, 4, 7, 8, 14 and 26.

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Table a15: cumulative shedding rate

¹ N (%)/N, ne=is not evaluable. In the case of NE, a warning occurs due to non-chi-square distribution. Individuals who missed one or several visits, and individuals who later re-entered the study, were not considered shed until all remaining visits were missed.

Table a16: compliance mean (standard deviation)

	EMP16 120mg/40mg(n＝45)	EMP16 150mg/50mg(n＝46)	Placebo (n=49)
				Compliance (%)	94.82(10.17)	95.71(5.17)	93.46(9.92)

There was no difference between the groups (data not shown).

Discussion of results

Of 156 randomized participants, 149 constituted the improved ITT population and were evaluated for their primary endpoint, and 135 completed a 28 week trial period. The PP population consisted of 122 participants in the treatment group. A total of 111 women and 45 men were randomly assigned in the trial. At baseline, there was no significant difference between the three groups (table 1).

As shown in fig. 2, participants treated with two doses of EMP16 for 26 weeks lost more body weight than participants treated with placebo (p < 0.0001). The average relative weight loss for the EMP16-120/40 ITT population was 5.33% and placebo was 0.83% (estimated treatment variance-4.70 (95% confidence interval-6.16 to-3.24; table 2)). More participants in the active treatment group reduced at least 5% and 10% of their baseline body weight at week 26 (fig. 3). Similar weight loss also occurs in PP populations or using more conservative interpolation methods. Participants treated with two doses of EMP16 for 26 weeks had significantly reduced BMI and waist circumference absolute average values compared to placebo participants (table 3). Participants treated with EMP16-150/50 had significantly reduced absolute average sagittal diameter and body composition (expressed as percent body fat) than those treated with placebo, whereas the reduction in the group treated with EMP16-120/40 had no statistical significance.

At week 26, there were no significant therapeutic differences in the absolute mean changes of glucose metabolic markers (fasting glucose, insulin, hbA1 c) or vital signs from baseline (table 3). At week 26, the lipid metabolism markers LDL and HDL cholesterol and total cholesterol (non-triglycerides) showed a small but statistically significant decrease compared to placebo. At week 26, there were no significant therapeutic differences in the changes in T2DM or pre-diabetic status from baseline.

Overall, there was no difference in satiety and total dietary impulse scores between the active treatment group and placebo group at week 26 (table 4).

Also, most participants appeared to follow the advice of healthy eating habits at baseline, and no therapeutic differences were observed in the overall diet pattern. At week 26, the EMP16-150/50 group had improved eating habits related to confections (biscuits, chocolate, candy, chips, soft drinks) and breakfast compared to placebo group, but the EMP16-120/40 group did not.

According to the RAND-36 wellness survey, the quality of life of both active treatment groups improved more in physical function, overall health, and overall health transition scores than the placebo group from baseline to 26 th period (table 4). Furthermore, the participants in the EMP16-150/50 group improved more in terms of physical pain, energy/fatigue and emotional well-being than those in the placebo group. During the trial, there was no difference in activity and sleep habits between study groups.

At week 26, the average score for GRSR diarrhea and dyspepsia syndromes was significantly higher in both active treatment groups compared to placebo group (table 4). Most participants rated their symptoms as mild or moderate. No therapeutic differences were observed in other parts of GSRS.

A total of 191 AEs were reported by 101 out of 156 randomized participants (65%), with the three most common events being nasopharyngitis, diarrhea, and headache (table 5). Diarrhea was reported only in the active treatment group. 4 of the 52 participants in the EMP16-120/40 group (7.7%) and 5 of the 52 participants in the EMP16-150/50 group (9.6%) were previously withdrawn from the trial due to gastrointestinal related AE. In addition, 1 participant in the EMP-150/50 group continued to participate in the trial as a result of withdrawal from infection with new coronaries. No participants in the placebo group were withdrawn due to AE, whereas the overall withdrawal rate of the active treatment group was comparable to that of the placebo group. Most AEs were mild or moderate in intensity. No mortality or serious adverse events occurred during the trial. Compliance was high and no differences were observed between treatment groups.

During the test, no clinically significant changes in liver enzymes occurred. A short increase occurs in a few people; however, according to the investigator's statement, these were considered independent of IMP, and participants continued to participate in the trial. During the trial, no clinically relevant or statistically significant changes or differences in the safety laboratory parameters or electrocardiography occurred (data not shown).

In this trial, EMP16 treatment for 26 weeks resulted in stable and clinically relevant weight loss. More than 50% of the participants in the two active treatment groups lost at least 5% of the baseline body weight, more than 20% of the participants were reduced by at least 10%, in contrast to 14% and 2% of the participants in the placebo group, respectively. Other anthropometric results, such as BMI, waist circumference, sagittal diameter and percent body fat, showed similar therapeutic effects, although the higher dose EMP16-150/50 was more effective. The quality of life reported by patients improves in both intervention groups, especially in terms of physical functioning, overall health and overall health transition scores. Blood pressure, glucose metabolic markers and blood lipid were not significantly affected, nor were therapeutic differences observed in satiety and degree of dietary impulses, although slight improvements in meal patterns associated with desserts and breakfast were found in the EMP16-150/50 intervention group. The EMP16 overall tolerability was good and no safety issues were found.

The results of the previous EMP16 pilot test, which demonstrated improved efficacy and tolerability of both orlistat and acarbose by using modified release intervention, were confirmed. Conventional dosage forms of orlistat and acarbose treatment generally provide relative weight loss of about 2-3% and less than 0.5% respectively, whereas placebo-adjusted mean weight loss observed in the EMP16 group is about 5%. The efficacy of EMP16 appears to be comparable to most currently approved weight loss drugs. Furthermore, conventional dosage form combinations of orlistat and acarbose may lead to tolerability problems and may increase their associated GI side effects such as flatulence with or without excretion. The design of EMP16 includes three influencing factors: (i) The action mechanism of the conventional dosage forms of orlistat and acarbose on energy absorption; (ii) A modified release profile is employed to ensure delivery of the food-derived ligand in a suitable manner to the various appetite regulating checkpoints in the gastrointestinal tract; and (iii) improved tolerability.

While weight loss can be achieved with EMP16, there is limited impact on blood pressure, glucose metabolism, and blood lipids. However, it is apparent from the baseline characteristics that this is a fairly healthy obese population. The prevalence of hypertension at baseline is about 30%, while the prevalence of obese patients is typically about 60%. Furthermore, baseline blood lipid levels were generally lower in this study, with only a small percentage of people (7%) taking hypolipidemic drugs and most participants had baseline HbA1c values below 40mmol/mol. The observed lack of clinically relevant changes in metabolic risk markers is consistent with studies of similar weight loss in non-diabetic obese patients using liraglutide or semaglutin (semaglutin).

The quality of life reported by patients in the intervention group, especially in the EMP16 150/50 group, has significant clinically relevant differences in several areas of RAND-36. The differences recorded were greater than those seen in other weight loss studies using conventional dosage forms of orlistat or liraglutide.

The dramatic improvement in quality of life scores is somewhat unexpected, and the link between weight loss and health score improvement can be seen in a exploratory post-hoc analysis. However, since the variance of the interpretation is low, the improvement in quality of life score must involve other factors in addition to weight loss.

There was no significant treatment difference in scores for satiety and dietary impulse. In pilot studies, the EMP16 group had a stronger feeling of satiety than conventional orlistat. As previously mentioned, conventional dosage forms of orlistat are associated with increased appetite compared to placebo, in part because of their effect on duodenal satiety cells (satiety sensing cell). The orlistat mediated effect on appetite appeared to be reduced following use of the MR formulation in EMP 16.

While participants in the EMP16-150/50 group reported an increase in breakfast intake and a decrease in candy and cake intake, no large treatment differences were observed in the reported meal pattern. This may be the "push" (nudging) effect of EMP16, as side effects are exacerbated if desserts, high fat foods are consumed, whereas in the EMP16-150/50 group the "cost" of incorrect diets appears to be higher. Alternatively, EMP16 may trigger an incretin effect (incretin effect) affecting participants' preferences for candies and cakes. In the previous 14-day pilot trial, we did not observe any effect on GLP-1. However, obese participants may require longer, higher doses to elicit an incretin response. '

Conventional dosage forms of orlistat and acarbose are associated with common gastrointestinal side effects, which limit their popularity. In this trial, 15% of the participants receiving EMP16 treatment reported diarrhea, while none of the placebo group reported diarrhea, and more individuals (6-8%) in the EMP16 group reported flatulence than the placebo group (2%). Since gastrointestinal events were recorded as AEs in the trial only when the investigator judged severe or caused withdrawal (withdrawal), some cases of mild or moderate gastrointestinal events were not registered. The results of GSRS confirm that the frequency of diarrhea for EMP16 is higher than placebo, but that the diarrhea syndrome score is around 3 points for both intervention groups (mild discomfort). Participants in the active group also rated GSRS dyspepsia syndrome as mild discomfort. A value below 2 (slight discomfort) generally indicates normal stomach function. ^18,28 Fecal incontinence is probably the most problematic side effect with conventional orlistat, but this does not appear to be a problem in this trial, with only one reported event in the EMP16-150/50 group, although of severe intensity. In a similar trial for 6 months, 5% of the participants in the conventional orlistat group reported fecal incontinence, while in the longer trial about 18% reported such events. Finally, only one participant reported nausea and no one reported vomiting, in contrast to studies with liraglutide.

This is a proof of concept test where there is limited interaction with the participants; the number of visits is small and the activity is limited. Furthermore, the participants did not receive any lifestyle instructions, only limited information about diet selection. Unlike many weight loss studies, no running-in participant selection procedure was used prior to randomization. One of the reasons for this "lean" design is to simulate real life situations and better understand the efficacy of EMP16 in an environment closer to clinical situations, somewhat similar to phase IV trials. The design chosen probably accounts for the limited placebo effect and ensures that the test can be performed during a new coronal pneumonia pandemic without any major disruption. Only the last visit of a few participants was delayed by one more week.

One limitation of this test (not exclusively of EMP 16) is the potential problem of maintaining masking, particularly because one of the known side effects of conventional orlistat is oily stool. Participants who guess themselves to receive placebo may have less motivation to complete additional lifestyle indications, which may lead to increased differences in outcome between active treatment and placebo. However, there was no difference in compliance between the treatment groups, and the withdrawal rates were low (15%) for all groups.

Another weakness of the trial is the interpolation method chosen. The LOCF interpolation method has been specified in advance in the scheme and has been recommended by the regulatory body before, but is no longer considered as the optimal method. A more conservative interpolation method is added afterwards and comparable (compatible) results are obtained.

In general, this test supports that orlistat and acarbose can be successfully combined as a promising potential drug candidate for improved weight management. The magnitude of weight loss may be less than that achieved using the plug Ma Gelu peptide (semaglutinide). However, as described in the canadian guidelines for obesity, "the individual's response to obesity management medications is diverse (hepatogenic); different patients may respond differently to the drug, so more tools in the kit would benefit only obese individuals. In addition, obesity is a chronic disease that may require long-term treatment. Both orlistat and acarbose in conventional dosage forms have demonstrated long-term safety. Safety issues were not observed in the current EMP16 test and overall, the safety and tolerability of modified release drug products appeared to be improved compared to conventional products. The effectiveness and safety of EMP16 remains to be assessed in a more diverse population for a longer period of time.

Quality of life

RAND-36

The RAND-36 health questionnaire includes 36 questions. The questionnaire investigates eight health concepts: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception. It also includes a separate item that provides an indication of the change in health perception. A low score indicates poor quality of life associated with health, while a high score indicates good quality of life associated with health.

In the EMP-120/40 group, from baseline to week 26, the average absolute value of 3 out of 8 areas (physical function, role limitation due to physical health problems, and general health) increases by 3 points or more. Also, the average score of 4 out of 8 areas (physical function, role limitation due to physical health problems, general health and energy/fatigue) increased by ≡10% from baseline. The overall health transition average score increased by 18.5 points, corresponding to a relative increase of 41.3%.

The differences between the EMP-120/40 group and the placebo group were statistically significant in several areas (domains): physical function (p=0.0076 [ absolute change from baseline ] and p=0.0131 [ relative change from baseline ]), overall health (p=0.0171 [ absolute change from baseline ] and p=0.0180 [ relative change from baseline ]), and overall health transition average score (p=0.0058 [ absolute change from baseline ] and p=0.0138 [ relative change from baseline ]), see tables 14.3-35.

In the EMP-150/50 group, the average absolute value of 7 out of 8 areas (physical function, role limitation due to physical health problems, physical pain, general health, energy/fatigue, social function, and role limitation due to emotional problems) was increased by 3 points above the baseline. Also, the average score for all areas, except for emotional well-being, increased by ≡ 10% relative to baseline. The overall health transition average score increased by 16.5 points, a relative increase of 48.4%.

The differences between the EMP-150/50 group and placebo group were statistically significant in several areas: physical function (p=0.0019 [ absolute change from baseline ] and p=0.0024 [ relative change from baseline ]), pain (p=0.0134 [ absolute change from baseline ] and p=0.0278 [ relative change from baseline ]), general health (p=0.0003 [ absolute change from baseline ] and p=0.0006 [ relative change from baseline ]), vigor/fatigue (p=0.0224 [ absolute change from baseline ] and p=0.0287 [ relative change from baseline ]), emotional health (p=0.0363 [ absolute change from baseline ] and p= 0.0390[ relative change from baseline ]), and general health transition average score (p=0.0111 [ absolute change from baseline ]) and p=0.0057 [ relative change from baseline ].

The average total score of placebo group in any area was not increased by 3 or 10% relative to baseline. The greatest positive change from baseline occurs in the body function domain (average absolute increase: 2.0 minutes, average relative increase: 3.8%). At week 26, the average total of the remaining fields was the same as or lower than baseline. Nonetheless, the overall health transition average score increased by 5.9 min/13.0%.

Conclusion(s)

Conclusion of efficacy

Treatment with two doses of EMP16 (120 mg orlistat/40 mg acarbose or 150mg orlistat/50 mg acarbose) for 26 weeks has a significant and clinically relevant effect on weight loss in obese patients. Patients treated with EMP16-120/40 or EMP16-150/50 had a weight loss of 5.8%/-5.75kg and 6.5%/-6.44kg, respectively, whereas patients with placebo had a weight loss of 0.7%/-0.78kg. Both doses of EMP16 produced greater proportions of patient weight loss of 5% or more and 10% or more, with significant impact on BMI and waist circumference reduction. Higher EMP16 doses also have a significant effect on the reduction of sagittal diameter and percent body fat.

EMP16 did not have any clinically relevant effect on empty glucose metabolism markers, lipid metabolism markers or liver enzymes compared to placebo, no significant effect on diabetes and pre-diabetic status of the patients, nor on blood pressure, as was reasonably expected in patient populations with low prevalence of hypertension and normal ranges of blood lipids and HbA1c, as described in EP-002 study.

Both doses of EMP16 have a significant positive impact on the health-related quality of life. Overall, there was no significant difference between treatment groups in appetite and overall eating habits, but EMP16-150/50 had a significant positive impact on confection intake and breakfast habits.

In this lean study, which was over 6 months, a significant synergistic effect was observed, as the relative weight loss achieved with two doses of EMP16-02 was more than twice that expected; as estimated from the addition of the values of the respective contributions of conventional orlistat and acarbose. In addition, the trend of the weight loss curve indicates that the nadir is reached only about 9-10 months. The model showed that the EMP16-02 group may lose about 6.5-7.0% of the relative body weight at 12 months, whereas the placebo group is likely to have returned to baseline levels. In addition, the body composition shows significant health benefits, reduced body fat proportions, and reduced waistline and sagittal diameters. The latter two are indicators of central fat accumulation (central adiposity), which are directly related to health outcomes. In addition, the compliance is high, the gastrointestinal side effect is less, and the shedding level is low. In this healthy obese population, the secondary outcome of the blood sample analysis was almost unchanged, which was unexpected. All previous experiments with orlistat and acarbose demonstrated their safety without alarming Serious Adverse Events (SAE) or Adverse Events (AE). No adverse results were observed in any of the safety variables.

Detailed description of the preferred embodiments

1. A composition of orlistat and acarbose for use in medicine, wherein the composition is orally administered to achieve a synergistic effect.

2. The composition for use according to item 1, wherein the synergistic effect is obtained after a period of treatment of 13 weeks or more, for example after a period of 14 weeks or more, after a period of 15 weeks or more, after a period of 16 weeks or more, after a period of 17 weeks or more, after a period of 18 weeks or more, after a period of 19 weeks or more, after a period of 20 weeks or more, after a period of 21 weeks or more, after a period of 22 weeks or more, after a period of 23 weeks or more, after a period of 24 weeks or more, after a period of 25 weeks or more, or after a period of 26 weeks or more.

3. The composition for use according to item 1 or 2, wherein the synergistic effect provides improved weight loss.

4. The composition for use according to claim 3, wherein the improved weight loss is at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% greater than the weight loss expected based on the additive effect (additive effect) of orlistat and acarbose.

5. The composition for use according to any one of the preceding claims, wherein the synergistic effect results in a weight loss of the subject of greater than 3%, such as greater than about 4%, greater than about 5%, or about 6%, based on the body weight of the subject prior to treatment.

6. The composition for use according to item 1, wherein the synergistic effect is obtained by administering orlistat and acarbose in a weight ratio ranging from 2:1 to 4:1 (e.g. weight ratio 3:1).

7. The composition for use according to any one of the preceding claims, wherein the combination is administered once daily, twice daily or three times daily.

8. A composition for use according to any one of the preceding claims, wherein the daily dose of orlistat for adults is 250mg or more, for example 270mg or more, 360mg or more, 450mg or more.

9. The composition for use according to any of the preceding claims, wherein the daily dose of acarbose for an adult is 75mg or more, for example 90mg or more, 120mg or more or 150mg or more.

10. The composition for use according to any one of the preceding claims, wherein the daily dose of orlistat is 120mg for children aged 5-10 with a weight of 40-60kg, 270mg for children aged 5-10 with a weight of 60-70kg, and the same daily dose of orlistat as for adults for children aged 10 and/or having a weight of more than 70 kg.

11. The composition for use according to any one of the preceding claims, wherein the daily dose of acarbose for a 5-10 year old child weighing 40-60kg is 60mg, the daily dose of acarbose for a 5-10 year old child weighing 60-70kg is 90mg, and the daily dose of acarbose for a child over 10 years old and/or weighing over 70kg is the same as for an adult.

12. A composition for use according to any one of the preceding claims comprising 90mg orlistat/30 mg acarbose, 120mg orlistat/40 mg orlistat or 150mg orlistat/50 mg acarbose.

13. The composition for use according to any one of the preceding claims, said combination comprising particles, spheres or pellets.

14. A composition for use according to any one of the preceding claims, comprising granules, spheres or pellets comprising an enteric coating of orlistat.

15. A composition for use according to any one of the preceding claims, comprising enteric coated granules, spheres or pellets comprising acarbose.

16. A composition for use according to any one of the preceding claims comprising modified release particles, spheres or pellets.

17. A composition for use according to any one of the preceding claims comprising three or four different moieties:

d) The fourth portion G3 comprises about 15 wt% to about 50 wt%, for example about 20 wt% to about 40 wt%, about 25 wt% to about 35 wt%, about 25 wt% to about 32 wt%, about 27 wt% to about 28 wt% or about 27.8 wt% of the total dose of orlistat, the total concentration of acarbose and orlistat being 100 wt%, respectively.

18. The composition for use according to item 17, wherein parts b) and c) are combined.

19. The composition for use according to item 17 or 18, wherein the concentration of acarbose in the first part G1 ranges from 25 wt% to about 50 wt%, such as from about 30 wt% to about 45 wt% or about 40 wt%, based on the total weight of the G1 part.

20. The composition for use according to any one of claims 17-19, wherein the concentration of acarbose in the second part G2A or G2 ranges from about 0.5 wt.% to about 4.5 wt.%, e.g. from about 1 wt.% to about 4 wt.%, from about 1.5 wt.% to about 3.5 wt.%, from about 2 wt.% to about 3.5 wt.%, from about 2.5 wt.% to about 3.25 wt.% or about 3 wt.%, based on the total weight of G2A or G2, as appropriate.

21. The composition for use according to any one of claims 17-20, wherein the concentration of orlistat in the G2B or G2 fraction ranges from 5 wt.% to about 30 wt.%, e.g., from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, from about 12 wt.% to about 20 wt.%, or about 15.5 wt.%, based on the total weight of G2B or G2, as appropriate.

22. The composition for use according to any one of claims 17-21, wherein the concentration of orlistat in the G3 fraction ranges from 20 wt.% to about 50 wt.%, such as from about 25 wt.% to about 50 wt.%, from about 30 wt.% to about 45 wt.%, from about 35 wt.% to about 45 wt.%, or about 40 wt.%, based on the total weight of G3.

23. The composition for use according to any one of claims 17-22, wherein the G2 moiety comprises a protective polymer at a concentration of at least 10 wt%, based on the weight of G2, such as 10-20 wt%, 12-20 wt%, 13-20 wt%, 13.5-20 wt%. G2A or G2B may be any suitable one.

24. A composition for use according to any one of the preceding claims comprising modified release particles, spheres or pellets comprising orlistat, wherein the modified release particles, spheres or pellets comprise from 30% to 50% by weight of orlistat.

25. A composition for use according to any of the preceding claims, comprising orlistat in micronized form, i.e. having an average particle size of less than 50 μm, such as less than 20 μm, such as less than 10 μm.

26. A composition for use according to any one of the preceding claims comprising modified release granules, spheres or pellets comprising from 35 to 60% by weight of cellulose or cellulose derivatives such as microcrystalline cellulose.

27. The composition for use according to any one of the preceding claims, comprising modified release granules, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80.

28. A composition as defined in any one of claims 17 to 27.

29. A method for obtaining a synergistic effect of acarbose and orlistat, the method comprising administering to a subject a modified release composition comprising acarbose and orlistat.

30. A method for achieving improved weight loss, the method comprising administering to a subject a modified release composition comprising acarbose and orlistat.

Claims

1. A composition comprising orlistat and acarbose for improving the quality of life of an obese or overweight individual.

2. A composition comprising orlistat and acarbose for use in the treatment of obese or overweight individuals, the treatment resulting in an improvement in quality of life.

3. Composition for use according to claim 1 or 2, wherein the obese or overweight individual has a BMI of 27kg/m ² Above, e.g. 29kg/m ² Above or 30kg/m ² The above.

4. Composition for use according to any of the preceding claims, comprising orlistat and acarbose in a weight ratio of 2:1-4:1, such as 180/60, 150/50 or 120/40mg orlistat/mg acarbose.

5. The composition for use according to any of the preceding claims, wherein the improvement of quality of life is assessed by a questionnaire comprising questions in the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception.

6. The composition for use according to any of the preceding claims, wherein the improvement of quality of life is assessed by RAND-36, SF-36, weight impact on quality of life (IWQOL), obesity and weight loss quality of life (OWLQOL) or similar health surveys.

7. A composition for use according to claim 5 or 6 for measuring an average overall health transition score.

8. The composition for use according to claim 7, wherein the improvement in the average overall health transition score is 10 points or more, such as 12 points or more, 14 points or more, 15 points or more, 16 points or more, as compared to baseline.

9. The composition for use according to any one of claims 5-8, wherein the improvement is an improvement in at least 5 of the following areas: physical function, physical pain, character limitation due to physical health problems, character limitation due to personal or emotional problems, emotional health, social function, energy/fatigue, and general health perception.

10. The composition for use according to any one of claims 5-9, wherein the improvement is measured in terms of an increase in physical function and/or general health.

11. The composition for use according to claim 9 or 10, wherein the improvement in average score is increased by more than 10 points from baseline.

12. The composition for use according to any one of claims 5-11, wherein the interval period of answering the questionnaire is at least 4 weeks, such as at least 8 weeks.

13. The composition for use according to claim 12, wherein the period of time is 26 weeks.

14. The composition for use according to any one of the preceding claims, wherein an improvement in quality of life is achieved regardless of the weight loss achieved by the individual during treatment.

15. The composition for use according to any one of claims 1-13, wherein the improvement in quality of life is achieved and the individual achieves at least 5% weight loss during treatment.

16. The composition for use according to any one of the preceding claims, wherein the composition is administered once, twice or three times per day.

17. The composition for use according to any one of the preceding claims, wherein the daily dose of orlistat during the treatment is 30mg to 540mg or more, such as 30mg to 450mg or more, 60mg to about 450mg or more, 90mg to about 450mg or more, about 120mg to 450mg or more, about 150mg to about 450mg or more, 180mg to 450mg or more, such as 180mg to 450mg, 270mg to 450mg, 360mg to 450mg or more for adults 270mg or more, 360mg or 450mg or more.

18. The composition for use according to any one of the preceding claims, wherein the daily dose of acarbose during the treatment is from 10mg to about 180mg, such as from 10mg to about 150mg, from 20mg to about 150mg, from 30mg to about 150mg, from 40mg to about 150mg, from 50mg to about 150mg, from 60mg to about 150mg, such as from 90mg to 150mg, 90mg or more, 120mg or more or 150mg or more.

19. The composition for use according to any one of the preceding claims, wherein the composition comprises 90mg orlistat/30 mg acarbose, 120mg orlistat/40 mg orlistat, 150mg orlistat/50 mg acarbose or 180mg orlistat/60 mg acarbose.

20. The composition for use according to any one of the preceding claims, wherein the treatment period is 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, such as 26 weeks, 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.

21. The composition for use according to any one of the preceding claims, wherein the composition comprises particles, spheres or pellets.

22. The composition for use according to any of the preceding claims, wherein the composition comprises orlistat in micronized form, i.e. having an average particle size of less than 50 μm, such as less than 20 μm, such as less than 10 μm.

23. The composition for use according to any one of the preceding claims, wherein the composition is an oral modified release composition comprising three or four different individual parts having different release patterns:

b) A second portion G2A comprising about 35% to about 55% by weight of the total dose of acarbose, for example about 35% to about 50% by weight, about 35% to about 45% by weight or about 40% by weight,

And the total concentration of acarbose and orlistat was 100 wt% respectively,

wherein-when the composition comprises three moieties, the three moieties are i) G1, ii) G2, wherein G2A and G2B are combined, and iii) G3.

24. A composition for use according to claim 23, wherein

ii) the G2A moiety is designed to release a fraction of the total acarbose dose in the duodenum and jejunum; the release should be relatively fast, since acarbose should exert its effect in the duodenum and jejunum,

iii) The G2B fraction is designed to release a fraction of the total dose of orlistat in the duodenum and jejunum; the release should be relatively rapid because orlistat should exert its effect in the duodenum and jejunum, and

25. The composition for use according to claim 23 or 24, wherein part b) and part c) are combined.

26. The composition for use according to any one of claims 23-25, wherein G1 is in the form of an inert core coated with a composition comprising acarbose, G2A and G2B are combined into G2, G2 is in the form of an inert core coating on which acarbose and orlistat are coated, then a coating with a protective polymer is provided, then coated with an enteric coating, G3 is in the form of uncoated granules.

27. The composition for use according to claim 26, wherein the protective polymer is selected from the group consisting of cellulose, cellulose derivatives and hydroxypropyl methylcellulose.

28. The composition for use according to any one of claims 23-27, wherein the G2A and G2B moieties are combined into G2, the G2 comprising a protective polymer concentration of at least 10 wt%, such as 10-20 wt%, 12-20 wt%, 13-20 wt%, 13.5-20 wt%, based on the total weight of G2.

29. The composition for use according to any one of the preceding claims, wherein the composition comprises modified release granules, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80.

30. The composition for use according to any one of claims 23-28, wherein the G3 moiety comprises modified release granules, spheres or pellets comprising 30-50 wt% micronized orlistat, 35-60 wt% microcrystalline cellulose and 10-18 wt% polysorbate 80.

31. The composition for use according to any one of claims 23-30, wherein the concentration of acarbose in the first part G1 ranges from 25 wt.% to about 50 wt.%, such as from about 30 wt.% to about 45 wt.% or about 40 wt.%, based on the total weight of the G1 parts.

32. The composition for use according to any one of claims 23-31, wherein the concentration of acarbose in the second fraction G2A or G2 ranges from about 0.5 wt.% to about 4.5 wt.%, such as from about 1 wt.% to about 4 wt.%, from about 1.5 wt.% to about 3.5 wt.%, from about 2 wt.% to about 3.5 wt.%, from about 2.5 wt.% to about 3.25 wt.%, or about 3 wt.%, based on the total weight of G2A or G2, as appropriate.

33. The composition for use according to any one of claims 23-32, wherein the concentration of orlistat in the G2B or G2 fraction ranges from 5 wt.% to about 30 wt.%, such as from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, from about 12 wt.% to about 20 wt.%, or about 15.5 wt.%, based on the total weight of G2B or G2, as appropriate.

34. The composition for use according to any one of claims 23-33, wherein the concentration of orlistat in the G3 fraction ranges from 20 wt.% to about 50 wt.%, such as from about 25 wt.% to about 50 wt.%, from about 30 wt.% to about 45 wt.%, from about 35 wt.% to about 45 wt.%, or about 40 wt.%, based on the total weight of G3.

35. The composition for use according to any one of claims 23-34, wherein the composition comprises modified release particles, spheres or pellets comprising 35-60 wt% cellulose or cellulose derivatives such as microcrystalline cellulose based on the total weight of the modified release particles, spheres or pellets.

36. Use of a composition comprising orlistat and acarbose for improving the quality of life of an obese or overweight individual.

37. The use according to claim 30, wherein the composition is as defined in any one of claims 23 to 35.

38. Use according to claim 36 or 37, wherein the improvement of quality of life is as defined in any one of claims 1-15.