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Title:
PHARMACEUTICAL FORMULATIONS COMPRISING LIPASE INHIBITOR
Document Type and Number:
WIPO Patent Application WO/2008/082373
Kind Code:
A2
Abstract:
This invention describes a pharmaceutical oral dosage formulation that is used in the treatment of obesity, comprising stomach and pancreas lipase inhibitor Orlistat.

Inventors:
USLU ABDULLAH (TR)
Application Number:
PCT/TR2007/000152
Publication Date:
July 10, 2008
Filing Date:
December 28, 2007
Export Citation:
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Assignee:
NOBEL ILAC SAN VE TIC A S (TR)
USLU ABDULLAH (TR)
International Classes:
A61K9/16; A61K31/337; A61K31/365
Domestic Patent References:
WO2000009123A12000-02-24
Foreign References:
EP0921796A11999-06-16
EP1216025A12002-06-26
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Claims:

CLAIMS

1- A pharmaceutical dosage form comprising at least one pharmaceutically active lipase inhibitor or its pharmaceutically acceptable salt as an active substance, and characterized by coating this active substance and at least one excipient on a neutral pellet together.

2- A pharmaceutical dosage form according to Claim 1, comprises a pharmaceutically acceptable lipase inhibitor coated with suitable excipients on neutral pellets by a method other than extruder spheronization or fluid bed with rotor granulation system included.

3- A pharmaceutical dosage form according to any one of the Claims 1-2, comprising a pharmaceutically acceptable lipase inhibitor coated with suitable excipients on neutral pellets by Fluid Bed which does not contain rotor granulation system and without using granulation technique.

4- A pharmaceutical dosage form according to Claims 1-3, the lipase inhibitor that is coated on neutral pellets, is Selected from the group comprising Orlistat, lipstatine, panclicines, hesperidins, ebelactones, valilactones or their derivatives.

5- A pharmaceutical dosage form according to Claim 4, lipase inhibitor is Orlistat.

6- A pharmaceutical dosage form according to Claims 1-5, the neutral pellets can be prepared with glucose, starch or other acceptable excipients.

7- A pharmaceutical dosage form according to Claims 1-6, Orlistat, coated on neutral pellets by a pharmaceutically suitable technique, can be coated as mono layer or multi layers.

8- A pharmaceutical dosage form according to Claims 1-7, coated on neutral pellets as mono layer or multi layers, is coated by Fluid Bed method.

9- Use of a pharmaceutical dosage form according to Claims 1-8, which comprises about 60 to 180mg, preferably 120mg Orlistat for the treatment of obesity and obesity related diseases.

- A pharmaceutical dosage form according to Claims 1-9, used in the treatment of obesity and obesity related diseases, which comprises 60 to 180mg, preferably 120mg Orlistat, is in the form of capsule.

Description:

DESCRIPTION

PHARMACEUTICAL FORMULATIONS COMPRISING LIPASE INHIBITOR

Technical Field:

Obesity takes the second place among the reasons of preventable death in early ages, after smoking, and it is also related to a lot of common fatal conditions such as type II diabetes, hypertension, cerebrovascular and cardiovascular diseases, gallstones, respiratory function disorders and cancer.

The formulation in this invention, which comprises lipase inhibitor, can be used not only in obesity treatment but also in other pathological treatments related to lipid metabolism including extreme weight gain cases like type II diabetes and syndrome X. Lipase inhibitors, alpha-glycosidase inhibitors (acarbose, AO-128) and newly developed intestinal glucose and fat absorption inhibiting pramlyntide (human amyline analogue) and exenatide (glycogen- like-peptide 1 receptor agonist) agents can be an important option in the treatment of obesity.

Type II diabetes is one of the most important life-shortening disease relating to obesity. In obesity, usually insulin resistance occurs, causing diabetes to reveal explicitly. High blood sugar levels cause serious organ destruction. High, systemic and pulmonary blood pressure are highly fatal secondary pathology that increases heart's work and induce heart failure. Fatty liver hepatosteatonecrosis is a co-morbid event with obesity. Inflammations in the joints and vertebral hernia caused by the elevated body weight, respiration difficulties and in relation sleep apnea caused by the ascended fat tissue on tongue and neck, gastroesophageal reflux, depression, anxiety, impotence, menstrual disorders, involuntary urination are other common pathologies that effect life quality in the illness of obesity. All cases mentioned above displays the importance of the treatment of obesity as a serious medical problem.

The obesity treatment with diet and changes in the life-style is usually insufficient, which proves that the patient also needs pharmacological support. For a lot of obese patients, medical treatment is effective for maintaining the development supplied by diet and change in the life-style for longer.

In the development of obesity, prevention of the digestion and metabolization of the diet fats is an important step. Getting excess fat than the body's need for the basal metabolism and its physiological functions is an important factor for the obesity to occur and continue. Nowadays, the fat percentage in nutrition is higher but in contrary the energy consumption is low for individuals because of the sedentary life style.

For that reason the medicines preventing the absorption of the fat of the nutrients from the intestines, are very important to take a major part in the treatment of obesity. Orlistat, preventing the intestinal lipid absorption and ezetimib, preventing cholesterol/sitosterol absorption, are important pharmacological agents being sold in the market.

Lipases play role in the digestion of the nutritional long-chain fatty acids. Gastric and pancreatic lipases hydrolyze every triglyceride molecule entering to the gastrointestinal channel and form two molecule fatty acid and one molecule monoglyceride for each. This enzymatic procedure makes the fat absorbable. Intestinal lipase inhibition is a recycled process because of the continued lipase synthesis in the pancreas and intestinal lining.

Gastric lipase is the most important pre-duodenal lipase and it activates the pancreatic lipase providing formation of fatty acids from the nutritional triglyceride. Pancreatic lipase has the mission to be the key enzyme for the digestion of nutritional triglyceride. Carboxyl ester lipase is another powerful lipolytic enzyme and it hydrolyzes the cholesterol esters to tri-, di- and mono-achylglycerols, phospholipids, lyzophospholipids and ceramide.

The inhibition of lipase activity by orlistat and its analogous, causes the blockage of digestion of the nutritional triglyceride, as a consequence, of the cholesterol solubility decreases and these molecules cannot be absorbed by the gastrointestinal system.

After the realization of the important pharmacological potential of lipase inhibition, Orlistat and followingly different lipase inhibitors like lipstatine, panclicynes, hesperidins, ebelactones, esterastin, their analogous and valilacton are developed. Orlistat is on the market for many years as an effectiveness and safety proven compound.

Orlistat is an oxetanone derivative obtained by hydrogenation of natural lipase inhibitor 'lipstatine' produced by Streptomyces toxytricini.

The use of orlistat for the obesity treatment is first explained in United States patent US4598089. Orlistat is N-formyl-L-leucine ester of "(3S, 4S)-3-hexyl-4-[(2S)-2- hydroxytridecyl]-2-oxetanone" and (-)-tetrahydrolipstatine and orlipastat names are also used in some resources.

This compound binds by covalent bonds to the serine parts of both the lipases secreted from stomach and pancreas in gastrointestinal channel and the pancreatic carboxyl ester lipases. This binding eliminates the chemical function of the enzyme. As a result, lipase cannot convert the nutritional lipids into mono-achylglycerols and free fatty acids, so absorption of the fat molecules from the villuses of the intestine cannot occur.

Other digestion hydrolases like amylase, trypsin, chimotrypsin, phospholipases, lipoprotein lipases and hepatic triglyceride lipases cannot be inhibited by orlistat.

Application of the daily dose of Orlistat is divided into 2 or 3 and taken together with meals. When taken with fatty meal, it partially inhibits the triglyceride lipolyze and develops the hypolipidemic effect. Most of the oral medicine is discarded by feces. Since the enzyme inhibition reaches to saturation, it has been realized that there is no additional contribution for the daily dosages exceeding 360 mg. Therefore, the most preferred dosage is 3 times 120 mg's daily. In order to be efficient, the medicine must be taken together with meals. There is no benefit in taking Orlistat if the meal has been skipped. The criteria for the use of the medicine is to be extremely fat or obese, in other words, the body mass index should be (BMI) > 30 kg/m 2 or in the presence of other risk factors (ex. Hypertension, diabetes, dislipidemia) (BMI) > 27 kg/m 2 . For the success of the treatment, the above mentioned obese patients must also obey the rules of diet and exercise program given.

The pharmaceutical dosage form comprising tetrahydrolipstatine and lipstatine has first been explained in EP0575846B1. In this invention, water insoluble fibrous structures like cellulose or biopolymers are used in the formulation together with tetrahydrolipstatine/lipstatine.

An Orlistat formulation providing a better qualified pharmacological activity obtained through the application of different surface-active materials, has been described in the patent EP1216025B1. According to the invention, surface-active materials provide fast dispersion of the formulation ingredients in the stomach.

Orlistat is very sensitive against environmental moisture and temperature (because of it's low melting point at 44 0 C). Preparation of solid dosage forms of Orlistat in tablet or hard gelatin capsule, is not possible because of the picking and sticking during the tablet pressing or capsulation process. It is very important to provide stabilization against these properties during the preparation and storage of the products containing moisture and temperature sensitive Orlistat. The temperature coming out during the tablet pressing process is an important risk for Orlistat. Therefore, pellet form is preferred in the formulations. The current formulation in the market is also in pellet form. These pellets are prepared by special equipment having cooling systems. The pellet formulation comprising Orlistat is first explained in patent EP0921796B1. According to this invention, Orlistat has been prepared as pellets having a diameter of 0.2-2 mm and consisting of polyvinylpyrolidone, microcrystalline cellulose and at least one pharmaceutical excipient. In this patent, orlistat turns into pellets by "extruder spheronizer". But alternatively the possibility of pellet preparation by 'fluidized bed having rotor granulation system' is pointed out. Although "Extruder spheronizer" method prevents the 'picking and sticking' phenomena a bit, during the preparation of pellet, this three-step production method could have some inconveniences and deficiencies.

Pellets can be produced by plenty of different methods. Among these, coating the active substance on a natural core and extrusion spheronization methods are the most preferred ones. In the medical industry, extruder spheronizer (ES), rotor pan and fluid bed are the most used devices for the preparation of pellets.

Coating the active material on a natural core can be applied in fluidized bed or coating pan. In this method, the active material which is in the form of suspension, solution or powder, coated

on the neutral core with the help of a suitable binder. Neutral cores generally are pellets made of starch and sucrose or microcrystalline cellulose.

The extrusion-spheronization method (ES) is a 3 step procedure. A typical extrusion and spheronization method consists of these steps:

The powder consisting of active substance and the excipients is wetted and a paste formed. The paste is pressed through a punched equipment (extruder) and spaghetti shaped moist strips are formed. Then these strips are broken up in a vertical cylinder (spheronizer) and spherical particles are obtained. Obtained spherical particles are dried in a suitable dryer. Preferably, the dry spheres are passed through a suitable sieve to obtain homogenous sized particles. As it can be understood from the description, ES is a multiple step production method carried out with multiple equipments.

Rotor Granulator included Fluid Bed contains a special container and a twirling fan. There is an air flow between the fan and the wall of the container. At this procedure, powder mixture is loaded to the container and the granulation solution sprayed on the mixture with a spray gun. But the procedure takes long time and the scale up procedure has difficulties.

In this invention Fluid Bed with Rotor Granulator is not being used. Also no other granulation procedure is made. Orlistat active ingredient is coated on the neutral pellets by using appropriate excipients.

In both ES and Fluid Bed Granulation methods, neutral pellets are not being used. In these methods, the lipase inhibitor and the excipients are mixed, a paste is formed by granulation of this mixture and then, the paste is turned into pellets using an appropriate technique.

Description of the Invention:

The root of the invention is to prepare a more homogenous new pellet formulation which does not have a different clinical efficiency from the known products, but with an easier and faster method. According to this invention, the lipase inhibitor agent is preferably effective on gastrointestinal and pancreatic lipases and this agent preferably is Orlistat. The weight ratio of the lipase inhibitor in the composition can be between 1-50 %, preferably between 15-40 %.

In the present invention, in spite of orlistat lipstatine, panclicines, hesperidins, ebelactones, esterastin and derivatives of these and valilactone can be used.

Pellet form is preferred in the preparation of the formulation considering the physicochemical properties of the raw material. In medical appliance systems, pellet form has some technological advantages like better flowability, lower friability, narrower distribution in view of size difference, easier coating and achieving equal content in filling the capsules; therapeutic advantages like lower irritation of gastrointestinal system, lower side effects caused by the sudden dosage release, more homogenous distribution in the gastrointestinal system and less fluctuations in the medicine-blood concentrations. In addition, the other important effect on the treatment is decreasing in the variability in the speed of emptying of the stomach and transfer speed of the medicine.

In the present invention, orlistat is being dissolved in the alcohol and then coated on neutral pellets with the help of PVP, as binder, and other pharmaceutical excipients.

The patent invention is a more stable and a more homogenous form than the market form of the active substance, humidity and temperature sensitive Orlistat, and a faster method to prepare the pellet form with the help of fluid bed.

The developed orlistat formulation's fluid bed pellet process has important advantages compared to the extrusion spheronization method, the production method of the market form. The Orlistat pellets obtained by extrusion spheronization do not have homogenous size distribution, the appearances of the pellets change from large granules to non-smooth surfaced pellets. But in our method, uniform, homogenous appearance pellets are obtained. As mentioned in EP0921796, Orlistat has a very low melting point. Because of the low melting point, picking and sticking occurs which does not allow the use of the tablet form and filling the capsules with the powder mixture. Therefore, preparation of the pellet formulation is preferred. More homogenous and smooth pellets lessen this problem. So, pellets prepared by the present invention can be filled to the capsules easier and faster. EP0921796 mentions the critical importance of microcrystalline cellulose (MCC) use for the preparation of the pellets. Our formulation can be easily prepared by not using MCC.

Together with Orlistat appropriate excipients are used in this invention. These are neutral core, binders, fillers, surfactants, disintegrants, lubricants and glidants.

The neutral core consists of starch, glucose or neutral pellets that can act as neutral cores.

Binders can be hydroxylpropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrolidone or other acceptable pharmaceutical excipients like same.

Filling materials can be lactose, microcrystalline cellulose or other acceptable pharmaceutical excipients like same.

Surfactants can be sodium lauryl sulphate, poloxamer or other acceptable pharmaceutical excipients like same.

Lubricants and glidants can be magnesium stearate, talc, aerosol, and stearic acid or other acceptable pharmaceutical excipients like same.

In the present invention, neutral core, binders, fillers, surfactants, lubricants and glidants are not restricted with the ones mentioned above; all excipients that could have the same function can be used instead.

The pharmaceutical dosage form comprising lipase inhibitor explained in this invention can be used for mammals especially humans for the treatment of obesity by pharmaceutical means, on obese people who cannot loose adequate weight by diet and exercise, on people with the BMI value above 30 kg/m 2 and on people with the BMI value above 27 kg/m 2 having risk factors like hypercholesterolemia, hyperlipoproteinemia, atherosclerosis, cardiovascular diseases, coronary diseases, angina, heart failure, hypertension, post-myocardial infarction, stroke, diabetes, metabolic syndrome, etc. in pharmaceutical effective dosages.

Example 1

* It is not taken into consideration in the calculation because it evaporates during the process.

Preparation of the pellets: a) Ethyl alcohol is placed in a stainless steel container having a cooler. b) Polyvinylpyrolidone (PVP K30) is dissolved in ethyl alcohol firstly. After PVP is dissolved, Orlistat is added and dissolved (A). c) Sodium lauryl sulphate and talc are added to the solution (A) and dispersed (B). d) The prepared solution (B) is cooled to 10-15 0 C. e) Neutral pellets are taken into fluid bed. f) Cooled B solution is coated on neutral pellets in fluid bed.

During the coating procedure effective parameters like solution pump speed, atomize pressure, inflow air volume, air inflow temperature, product temperature and solution temperature can be adjusted.