JP2003513000A - Oral oil absorption composition - Google Patents

Abstract

  (57) [Summary] An oil absorption delivery system is described. The system has an oil absorbing reagent and is suitable for delivering the reagent to the small or large intestine of a mammal. The oil absorbing reagent may be calcium silicate or microcrystalline chitosan.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to compositions for use in obesity control. More particularly, the present invention relates to the unwanted dietary fat of the patient's small and / or large intestine,
In particular, it relates to compositions suitable for absorbing non-metabolized or unmetabolized dietary fat for treatment to patients with drugs that inhibit the enzymatic conversion of fat.

[0002]

[Prior art]

In many Western countries obesity is a significant problem for more than about 30% of adults considered clinically obese. Weight loss can be accomplished utilizing a diet or pharmacological agent. Unfortunately, both approaches are fat “
It can lead to adverse side effects such as “leakage” and “spotting”.

One approach to dietary weight loss involves the use of non-metabolizable fat substitutes such as Olesra. Olestra is Olean (
Trademarks), Procter and Gamble (New Eng. J. Med. 334 , 9).
84 (1996)). This material is a polyester of sucrose and six or nine triglycerides and can be used as a substitute for vegetable and animal fats. Olestra is
Adds the necessary texture and taste peculiar to fat, but with dietary lipa
ses) and is not absorbed in the intestine and consequently not absorbed. However,
If you consume large amounts of food, including olestra, excess fat can cause an anal sphincter (ana
l sphincter), causing embarrassment and even soiling clothes (Ano
n. Univ. California at Berkeley Wellness Lett. 12, 1-2 (986)).

In the body, fats (triglycerides) are composed of fatty acids and diglycerides.
It is enzymatically converted to des and these substances are then converted into bile salt micelles.
elle) and is substantially absorbed. One of the pharmacological treatments for obesity involves the use of drugs that inhibit the enzymatic conversion of fats into fatty acids and diglycerides,
Many drugs that cause such effects are under development. The mechanism is one of the preferential bindings with lipids, which interferes with the interaction with dietary lipids. Orlistat,
The compound of Merck Index, 12, Edition P.6998 is a pancreatic lipid reaction inhibitor (pancreati).
C lipase inhibitor) (Obes. Res. 3 Suppl. 4, 6235, 1995). However, when using olestra, the metabolism of dietary fat, which is weakened, for example, by the administration of lipid reaction inhibitors, will cause anal leakage of fatty substances.

The use of chitosan as a food additive or pharmacological preparation to reduce lipid absorption has been described in US-4,233,023. There is nothing in US-4,233,023 that chitosan would be supplied in the coated single unit dosage form to the terminal ileum, or colon. Not proposed. The examples given in US-4,233,023 describe foods and powders dispersed in water or a flavored vehicle before dosing.

[0006]

[Problems to be Solved by the Invention]

In this way, non-metabolizable dietary fat or degradation from the anal sphincter (bre
It would be advantageous to have a product that is capable of reducing or eliminating the leakage of unmetabolized dietary fat due to the use of drugs that inhibit akdown).

We have found that in the human small and / or large intestine, especially in the terminal ileum and / or proximal (proxima
It has been found that the above objects can be achieved by using a pharmacological composition which supplies an oil absorption reagent to the l) and transverse colon.

[0008]

[Means for Solving the Problems]

According to a first aspect of the present invention there is provided a composition comprising an oil absorption reagent, said composition being suitable for supplying said oil absorption reagent to the small or large intestine of a mammal, in particular a human. There is a composition.

According to a second aspect of the invention, an oil absorption delivery system comprising an oil absorption reagent, said system being suitable for supplying said oil absorption reagent to the small or large intestine of a mammal, in particular a human. There is an oil absorption delivery system that is characterized by

“Oil absorbing reagent” means 0.5 to 25 ml of oil per gram when contacted with the oil as a simple substance or as an oil dispersed in an aqueous medium having a pH of 5 to 8 or so. A substance that absorbs. The oil absorbing reagent is preferably capable of absorbing 1 to 20 ml of oil per gram, more preferably 2 to 10 ml of oil.

The term “oil” includes fats and dietary fats, fatty acids, triglycerides, non-metabolizable oils and fats.

In order to interact with dietary fat, the small intestine and / or the large intestine, especially the terminal ileum and / or
Or, the oil-absorbing reagents released into the proximal and transverse colon are diverse in nature. Dietary fat is an oily substance (oleaginous) that is a constituent of foodstuffs that is not absorbed in the small intestine.
material) is meant. The term includes olestra as well as vegetable and animal fats.

Suitable oil-absorbing reagents are calcium silicate, microcrystalline cellulose
(microcrystalline cellulose) (Avicel ™), dried aluminum hydroxide gels, microcrystalline chit
osan) (described by Struszczyk, J. Appl. Polymer Sci. 33 , 177 1987, and available from Novasso OY, Finland), charcoal, and product AST.
-120 porous carbon adsorbants (Japanese Kurela Ch
Available from emical Industry Co. Ltd. and J. Pharm. Pharmac. 49 657 (
1997)).

The dosage of a suitable oil absorption reagent to a patient is in the range of 1 to 10 g per day. Furthermore, it is preferred that 1 to 5 g per day be administered to the fasted stomach.

Calcium silicate is a particularly preferred oil absorbing reagent. Porous calcium silicates that absorb oil are well known as Florite and are available from Eisai Co. Ltd. of Japan. This material is specified to absorb 5 ml of oil per gram of absorbent. Calcium silicate is a pharmacological and food-use substance.

[0016]   A particularly preferred oil absorbing reagent is microcrystalline chitosan.

The composition / delivery system of the present invention may be a suitably coated single unit dosage form.

In one embodiment, a single unit dosage form comprises a core having an oil-absorbing reagent and a core covering the release of the oil-absorbing reagent or any substantial release until the tablet reaches the small or large intestine. tablet with an outer coating or layer with a substance that also interferes with release). Preferably, the coating provides a release of the oil-absorbing agent in the stomach and in the upper region of the small intestine, which means the duodenum and jejunum, so that the release of the oil-absorbing agent does not occur until the tablet reaches the terminal ileum or large intestine, for example the colon. Suitable for hindering.

A tablet is a direct compression of an oil-absorbing reagent (usually in powder form).
n) Alternatively, prior to compression to form tablets, the powder is moistened with a granular reagent, such as water, alcohol, or sugar solution, and then, for example, in a dry heat sterilizer (hot-a).
It can be produced by a process involving granulation, such as passing the wet material through a sieve to produce wet granules that are dried in an ir oven. Dispersion or disintegration aids, such as sodium starch glycolate (Explotab (TM)), starch, lactose, croscarmellose s.
odium) (Ac-Di-Sol ™) can be added to the oil absorption reagent (Pha
rmaceutical Dosage Forms: Tablets Volumes 1 and 2, HA Lieberman, L. La
ckman and JB Schwartz (Eds), Marcel Dekker, Inc. New York 1989,).
. Its purpose is to provide sufficient mechanical strength for coating and subsequent handling to provide a good surface area for fat absorption, but to rapidly disperse in the small or large intestine, especially in the terminal ileum or colon. To produce a single unit system with an oil absorbing reagent that

In another embodiment, the single unit dosage form comprises a caging surrounding the compartment containing the oil-absorbing reagent and the release of the oil-absorbing reagent or any substance on the outer surface of the caging until the capsule reaches the small or large intestine. And a protective coating or layer with a substance that also impedes targeted release. Preferably, the coating is such that the release of the oil-absorption reagent does not occur until the tablet reaches the terminal ileum or colon, for example the colon.
The stomach and the upper region of the small intestine, which means the duodenum and jejunum, are suitable for blocking the release of oil-absorbing reagents.

In encapsulating the oil-absorption reagent, any capsule made to deliver a medicament to the human body may be used. A suitable capsule is hard gelatin.
gelatin), starch, or hydroxypropyl methylcellulose
(including methyl cellulose).

Starch capsules, such as those described, for example, in United States Pharmacopoeia (USP), are preferred because of their advantages in coating, ie the storage and stability of the coating layer. Resistant to the general condition of the upper region of the stomach and small intestine, such that the release of encapsulated oil-absorption reagent is prevented or substantially prevented until the capsule reaches the terminal ileum and / or colon. Starch capsules having an outer coating of a forceful substance are preferably used in the present invention. Such capsules are described in PCT / GB95 / 01458.

Starch capsules, like capsules made from starch, are modified starches.
Also included are capsules made from (modified starch) or starch derivatives. The term “derivative” is especially used, for example, for ionized groups.
roupings to include non-functional or functional parent compounds (parent com
pounds means esters and ethers.

A suitable starch derivative is hydroxyethyl starch.
, Hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch,
Includes succinate derivatives of starch, and grafted starches. Such starch derivatives are well known and are well described in the art (eg Modified Starches:
Properties and Uses, OB Wurzburg, CRC Press Boca Raton (1986)).

[0025]   The starch used should have food or pharmacological quality.

Starch capsules can be made by an injection molding process and generally have a body and a cap. The body is filled with an oil absorbing reagent and then capped and sealed. The method of making starch capsules is well known, for example EP-A-118240, WO-90 / 05161, EP-A-03044.
01, WO-92 / 04408, and GB-2187703.

A method of targeting the ileocaecal region and colon is PCT / US
91/02319, EP-A-0454383, EP-A-0366621, US-4,432,966, GB-A-2292079, PCT / JP
89/00748, PCT / US91 / 03014, PCT / SE91 / 00475, EP-A-0673645, US-4,663,308, WO
-90/13286, GB-A-2174599, PCT / GB89 / 00581, GB-A-2166051, EP-A-0621032 and Watts and Illum, Drug Dev. Ind. Pharm. 23 (9) 893-914, 1997 and Wilding e
t., Pharmac. Ther. 62 , 97, (1994).

The oil absorption reagent may be filled in a variety of known delivery systems targeting the ileocecal and colonic regions, including those described in the above references.

Alternatively, the oil-absorption delivery system comprises granules or pellets of the oil-absorption reagent, releasing the oil-absorption reagent or any substantial release until the granules / pellets reach the small intestine or the large intestine. It may also take the form of a capsule provided with an outer coating having a substance that also interferes with

The coating / layer in the delivery system described above may also be formed from an enteric material, such as an enteric polymer that slowly dissolves in the small intestine to expose the oil-absorbing reagent to a liquid in the terminal ileum and / or colon. Good. Alternatively, the coating / layer may be formed from a polymeric material that is not degraded until certain conditions within the colon are met. Such a degradation is, for example, a reduction condition (
direct chemical degradation, such as the degradation of disulphide bonds under reducing conditions, or the consequences of microflora found in the colon that can cause degradation of polysaccharide materials. chemical decomposition)
You may go through.

A preferred enteric coating material for targeting the ileocecal or colonic regions which may be used to coat capsules, tablets or pellets has a pH of 4.5 or higher, eg 5.0. It dissolves at the above pH. by this,
The coating remains in the stomach and begins to dissolve once it enters the small intestine. The thick layer of coating is preferably provided to dissolve in about 2 to 5 hours so that only when the terminal ileum and / or colon is reached the capsule shell or tablet core lower part ( tablet core underneath) is dispersed. Such coatings are available in a variety of polymers such as "Enteric Coatings an
d Delayed Release ", Chapter 7 in Drug Delivery to the Gastrointestinal T
Cellulose acetate trimellate as described by Henry in ract, eds. Hardy et al, Ellis Horwood, Chichester, 1989.
itate) (CAT), hydroxypropyl methylcellulose phthalate
ylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (poly)
vinyl acetate phthalate (PVAP), cellulose acetate phthalate
It can be prepared from cetate phthalate (CAP) and shellac. A thickness of 150 to 300 μm is suitable for coating the polymer.

Particularly preferred enteric substances are, for example, methyl methacrylate homopolymers (methy)
l methyl methacrylate residues such as
It is a polymer having acrylate residues and a copolymer of methyl methacrylate and methacrylic acid. Copolymers of methyl methacrylate and methacrylic acid are useful as Eudragit ™ enteric polymers (Rohm Pharma, Darmstadt, Germany).

A preferred composition is Eudragit L100 and E as described in PCT / GB95 / 01458.
It is based on the udragit S100. Eudragit S100 dissolves at pH 7 and above, but Eudgit
ragit L100 dissolves at pH 6 and above. A preferred coating composition has an L100 of 1.
Eudragit L100 and Eudragit S100 within the range of 0 part for S00 (100 parts L100: 0 parts S100) to L100 for 20 parts and S100 for 80 parts (20 parts L100: 80 parts S100) Is based on. The most preferable range is 70 parts for L100 and 30 parts for S100 (70 parts L100: 30 parts S100)
From L100 to 80 parts, S100 to 20 parts (80 parts L100: 20 parts S100
). As the pH at which the coating begins to dissolve increases, the thickness required to achieve specific delivery to the colon decreases. For formulations with a high Eudragit L100: S100 ratio, a coat thickness of about 150-200 μm is preferred. This is comparable to 70-110 mg coating for size 0 capsules. For coatings with a low Eudragit L100: S100 ratio, approximately 80 to 12
A coat thickness of 0 μm is preferred, which is 30 to 60 for a size 0 capsule.
Equivalent to mg coating.

The colonic region is the home of many microbial anaerob organisms that provide reducing conditions.
ic organisms). Therefore, the coating should be properly redox sensitive.
x sensitive) material. Such coatings are, for example, divinylazobenzene (divi) synthesized by free radical polymerisation.
Azopolymers consisting of random copolymers of styrene and hydroxyethyl methacrylate cross-linked with nylazobenzene) (azopolymers are enzymatically degraded, especially in the colon) Or disulphide polymers (P
(See CT / BE91 / 00006 and Van den Mooter, Int. J. Pharm, 87, 37 (1992))
May have.

Other substances that may be used to provide release in the colon are amylose (amy
lose) or its complex. For example, the coating composition comprises an ethyl cellulose aqueous dispersion (Ethocel ™) with an amylose-butan-1-ol complex (
It can be made by mixing glassy amylose) (Milojevic et al., J. Control. Rel., 38, 75 (1996)). The final coating may have an inner layer of glassy amylose and an outer layer of cellulose or acrylic polymer material (Allwood et al., GB9025.
373.3). Other suitable coating materials are calcium pectate.
nate) (Rubenstein et al., Pharm. Res., 10, 258, (1993)), colonic bacterial enzyme (c
pectin-polysaccharide (pect), which is totally degraded by olonic bacterial enzymes
in-a polysaccharide) (Ashford et al., Br. Pharm. Conference, 1992 Abst
ract 13), chondroitin sulphate (Rubenstein et al., Ph
arm. Res. 9, 276, 1992), dextran hydrogels (Hovga
ard and Brondsted, 3rd Eur. Symp. Control. Drug Del., Abstract Book, 199
4, 87), for example, modified guar gum such as borax modified guar gum (Rubenstein and Gliko-Kabir, STP Phar
ma Sciences 5, 41 (1995)), p-cyclodextrin (Sie ke
et al., Eur. J. Pharm. Biopharm, 40 (suppl), 335 (1994)), for example, cellobiose (cellobiose), lactulose, raffinose (raffinose),
Saccharides containing polymers containing methacrylic polymers covalently linked to oligosaccharides such as stachyose, such as cross-linked chondroitin sulfate and calcium pectate (cal
saccharides containing natural polymers containing modified mucopolysaccharides such as metal pectin salts such as cium pectate (Sintov and Rubenstein; PCT / US91 / 03014), methacrylate galactoate Manganese (galactomannan) (Lehmann and Dreher, Proc. Int. Int.
Symp. Control. Rel. Bioact. Mater. 18, 331 (1991)), pH-sensitive hydrogels (Kopecek et al., J. Control. Rel. 19, 121 (199).
2)), such as vitreous amylose, resistant starch that is not enzymatically degraded in the upper gastrointestinal tract but is enzymatically degraded in the colon.
s) (Allwood et al., WO-89 / 11269, 1989).

The composition / system of the present invention provides for the enzymatic conversion of fat into fatty acids and diglycerides.
It may be adapted to deliver a therapeutic agent, such as a drug that suppresses enzymatic conversion, to the small or large intestine of the gastrointestinal tract, such as the terminal ileum or colon region, especially the proximal colon. Preferably, means are provided to prevent release of the drug until the formulation reaches the colonic region.

Although the present invention is directed to treating the side effects of obesity treatment, it will be apparent to those skilled in the art that the present invention may be used to treat steatorrhea-causing diseases.

[0038]

DETAILED DESCRIPTION OF THE INVENTION

  The present invention has been illustrated, but is not limited to the following examples.

Example 1 Determination of in vitro fat binding properties of calcium silicate oil absorption reagent A method based on the method of Nauss et al. Cancer Res. 43 , 4083, (1983) was used. The oil absorption reagent was mixed with simulated intestinal contents.
The oil binding capacity of different substances is determined by using standard procedures, eg 0
． 5 g of Florite was mixed with 4 ml of sesame oil. The oil mixed well into the powder.
There was no evidence of free oil. Disperse 5 ml of vegetable oil (sesame oil) at pH
Dispersed in 50 ml of 7.00 buffer. Different amounts of the oil-absorption reagent are dispersed in the buffer system, and the amount of separated fat is determined by the use of standard analytical techniques such as the Saxon method to reduce the amount of fat remaining in the dispersed phase. Was determined by a binding isotherm determination. (See, for example, Richterich and Colombo, Clinical Chemistry, Wiley, 1981).

Binding studies with oil-absorbing reagents, which were later administered as powders in the buffer system, as well as in the form of uncoated single unit systems such as tablets or capsules dispersed in the buffer system. ) Was done.

[0041]   The oil was mixed well with the oil absorbing reagent. There was no evidence of free oil.

Example 2 Measurement of in vitro fat binding properties of microcrystalline chitosan oil absorption reagent 25 ml of water and sunflower oil (Sa) in each of two 50 ml measuring cylinders.
insbury's, London, UK). One gram of microcrystalline chitosan (Novasso Oy, Finland, molecular weight 150 kDa, deacetylation degree (
degree of deacetylation) 74%) was added. Both cylinders were stoppered, inverted 10 times and left to stand overnight. In the sample without microcrystalline chitosan, the oil formed a distinct phase on top of the water (Figure 1).
In the sample containing microcrystalline chitosan, most of the oil (greater than 20 ml) became globules approximately 1 to 5 mm in diameter (Fig. 1). Their stable droplet morphology appeared as a result of the accumulation of microcrystalline chitosan particles at the water-oil interface.

Example 3 Measurement of in vitro fat binding properties of microcrystalline chitosan oil absorption reagent (high viscous environment) 1.6% hydroxypropyl methylcellulose to mimic a system with a more comparable viscosity depending on the contents of the colon. An aqueous solution containing (HPMC) was prepared and 40
0 ml of water was warmed to 80 ° C and 16 grams of Mesocel E10M grade (Me
thocel E10M grade) HPMC was added (Colorcon, Orpington, UK). HP
The MC was dispersed in hot water and the dispersion moved to an ice bath. Stirring was continued until a sticky gel was formed. The mixture was separated from the ice bath and adjusted to 1000 ml with water. 200 ml of HPMC solution and 20 ml of sunflower oil were added to each of two glass beakers. 0.8 grams of microcrystalline chitosan (see Example 2) was added to one beaker. The contents of each beaker are thoroughly mixed,
After that I left it all night long. For samples that did not contain microcrystalline chitosan, the oil formed a distinct layer on top of the HPMC solution. For the sample containing microcrystalline chitosan, there was no apparent free oil on the beaker surface. The upper half of the beaker contents was yellow, suggesting that the oil was present in a dispersed form in this portion of the sample.

Example 4 Adsorption of fat by microcrystalline chitosan in the presence of stool material Feces were collected and pooled from 3 female crossbred pigs. The following formulations were evaluated in duplicate.

(1) 25 g of stool, 10 ml of soybean oil (CWS, Manchester, UK) and 10
0 ml water. (2) For (1), plus 1 g of microcrystalline chitosan (Novasso Oy, Finland
). (3) For (2), 2 g of microcrystalline chitosan was used.

The mixture was vigorously stirred and allowed to settle for more than 24 hours. A simple oil / water mixture was used as a control.

For samples that did not contain chitosan, 2 to 8 ml of oil was isolated (simplified).
e separation). Samples containing 1 g and 2 g of microcrystalline chitosan had no separated free oil present.

Example 5 Measurement of Fat Absorption In Vivo The effect of oil absorption reagents on stool excretion of fat in rats fed a high fat diet was determined by Deuchi et al. Biosci. Biotech. Biochem. 59 781 (
1995). In this method, an oil absorbing reagent is included in an experimental diet containing corn oil and lard (40%). Animals are on this diet for 13 days. Faecal li
pids) are standard methods (eg Saxon) (Richterich and Colombo, Clinical Chemi
Sts, see Wiley 1981) gravimetrically. A clear fat digestibility value is obtained.

The ability of the single unit dosage form and the oil absorbing reagent contained therein to effect fat adsorption in vivo is determined by using fistulated pigs. This pig has a fistula in the intestine in the area of the terminal ileum. This allows direct access to the large intestine, which is the human colon or ileocaecal junction.
It is a model suitable for evaluating systems that direct substances to junctions. The model used is Garner et al. J. Pharm. Pharmac. 48 , 689, (1996). The uncoated single unit is placed in the colon through an ileal fistula that can degrade the unit to release its contents. The pigs are fed a diet to provide steatorrhoea. Stool is collected 36 hours after administration using a metabolic cage system. Fecal fat content in treated and untreated animals is measured using standard analytical methods for fat content (eg Richterich and Col.
See ombo, Clinical Chemistry, Wiley, 1981).

Example 6 Tablet Dosing A tablet system was made by direct compression of 500 mg microcrystalline chitosan containing 25 mg croscarmellose sodium as a dispersing agent. Tablets were made by using a Manesty F3 machine with a 20 mm x 8 mm rectangular concave punch. The tablets were prepared with an enteric polymer (Eudragit L: S ratio of 3: 1 with plasticizer and talc in isopropanol 3: 1 to give a thickness comparable to the average tablet weight increased by 90 mg. ) Covered with a layer. The tablets were coated by the standard method of spray coating using an Aeromatic STREA-1 coater (standard column) with a drying temperature of 25 ° C., a blast speed of 6 and a spray pressure of 1 bar. A pan coater could also be used. Of tablets that remain intact at acidic pH (gastric state) and that release their contents after 2 hours in alkaline state (to simulate migration in the small intestine and release of adsorbent in the distal colon region) Capacity was determined using a standard USP dissolution instrument (Type 1) and using pH 2 and pH 6.8 buffers. The tablets were exposed to the acid state for 2 hours and held intact. After being exposed to alkaline conditions, the coating dissolved and the tablets released their contents.

Example 7 Capsule Administration Starch capsules (USP) were obtained from Capsugel, Switzerland. 5 capsules
It was filled with 00 mg of calcium silicate (Fluorite). The capsules were then coated as in Example 3 with a weight gain of 90 mg.

[Brief description of drawings]

BRIEF DESCRIPTION OF THE FIGURES FIG. 1: In a sample without microcrystalline chitosan, the oil formed a distinct phase on top of the water. In samples containing microcrystalline chitosan, most oil (> 20 ml)
Became droplets of approximately 1 to 5 mm in diameter.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] March 2, 2000 (200.3.2)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Contents of correction]

[0001]

FIELD OF THE INVENTION The present invention relates generally to compositions for use in obesity management. More particularly, the present invention relates to the unwanted dietary fat of the patient's small and / or large intestine,
In particular, it relates to compositions suitable for absorbing non-metabolized or unmetabolized dietary fat for treatment to patients with drugs that inhibit the enzymatic conversion of fat.

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

[Contents of correction]

[0002]

BACKGROUND OF THE INVENTION In many Western countries, obesity is a significant problem for more than about 30% of adults considered clinically obese. Weight loss can be accomplished utilizing a diet or pharmacological agent. Unfortunately, both approaches are fat “
It can lead to adverse side effects such as “leakage” and “spotting”.

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Contents of correction]

One approach to dietary weight loss involves the use of non-metabolizable fat substitutes such as Olesra. Olestra is Olean (
Trademarks), Procter and Gamble (New Eng. J. Med. 334 , 9).
84 (1996)). This material is a polyester of sucrose and six or nine triglycerides and can be used as a substitute for vegetable and animal fats. Olestra is
Adds the necessary texture and taste peculiar to fat, but with dietary lipa
ses) and is not absorbed in the intestine and consequently not absorbed. However,
If you consume large amounts of food, including olestra, excess fat can cause an anal sphincter (ana
l sphincter), causing embarrassment and even soiling clothes (Ano
n. Univ. California at Berkeley Wellness Lett. 12, 1-2 (1996)).

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Contents of correction]

In the body, fats (triglycerides) are composed of fatty acids and diglycerides.
It is enzymatically converted to des and these substances are then converted into bile salt micelles.
elle) and is substantially absorbed. One of the pharmacological treatments for obesity involves the use of drugs that inhibit the enzymatic conversion of fats into fatty acids and diglycerides,
Many drugs that cause such effects are under development. The mechanism is one of the preferential bindings with lipids, which interferes with the interaction with dietary lipids. Orlistat,
The compound of Merck Index, 12, Edition P.6998 is a pancreatic lipid reaction inhibitor (pancreati).
C lipase inhibitor) (Obes. Res. 3 Suppl. 4, 6235, 1995). However, when using olestra, the metabolism of dietary fat, which is weakened, for example, by the administration of lipid reaction inhibitors, will cause anal leakage of fatty substances.

[Procedure correction 6]

[Document name to be amended] Statement

[Name of item to be corrected] 0032

[Correction method] Change

[Contents of correction]

Particularly preferred enteric substances are, for example, methyl methacrylate homopolymers (methy)
l methyl methacrylate residues such as
It is a polymer having acrylate residues and a copolymer of methyl methacrylate and methacrylic acid. Copolymers of methyl methacrylate and methacrylic acid are useful as Eudragit ™ enteric polymers (Rohm Pharma, Darmstadt, Germany).

[Procedure Amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0033

[Correction method] Change

[Contents of correction]

A preferred composition is based on Eudragit ™ L100 and Eudragit ™ S100 as described in PCT / GB95 / 01458. Eudragit ™ S100 is p
It dissolves at H7 and above, whereas Eudragit ™ L100 dissolves at pH 6 and above. A preferred coating composition has 100 parts of L100 and 0 part of S100 (100 p
From arts L100: 0 parts S100), S100 is 80 parts (20 p for L100 20 parts)
arts L100: 80 parts S100) within a range of Eudragit (TM) L100 and Eudragit
Based on the trademark S100. The most preferable range is from 70 parts of L100 to 30 parts of S100 (70 parts L100: 30 parts S100) to 20 parts of L100 to 80 parts (80 parts L100: 20 parts S100). As the pH at which the coating begins to dissolve increases, the thickness required to achieve specific delivery to the colon decreases. For formulations with a high Eudragit ™ L100: S100 ratio, a coat thickness of about 150 to 200 μm is preferred. This is a size 0 capsule
Equal to 70 to 110 mg of coating for (size 0 capsule). Eudrag
About 80 to 120 for coatings with a low proportion of it ™ L100: S100
A coat thickness of μm is preferred, which is 30 to 60 m for size 0 capsules.
g coating.

[Procedure Amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Contents of correction]

The colonic region is the home of many microbial anaerob organisms that provide reducing conditions.
ic organisms). Therefore, the coating should be properly redox sensitive.
x sensitive) material. Such coatings are, for example, divinylazobenzene (divi) synthesized by free radical polymerisation.
Azopolymers consisting of random copolymers of styrene and hydroxyethyl methacrylate cross-linked with nylazobenzene) (azopolymers are enzymatically degraded, especially in the colon) Or disulphide polymers (P
(See CT / BE91 / 00006 and Van den Mooter, Int. J. Pharm, 87, 37 (1992))
May have.

[Procedure Amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0035

[Correction method] Change

[Contents of correction]

Other substances that may be used to provide release in the colon are amylose (amy
lose) or its complex. For example, the coating composition comprises an ethyl cellulose aqueous dispersion (Ethocel ™) with an amylose-butan-1-ol complex (
It can be made by mixing glassy amylose) (Milojevic et al., J. Control. Rel., 38, 75 (1996)). The final coating may have an inner layer of glassy amylose and an outer layer of cellulose or acrylic polymer material (Allwood et al., GB9025.
373.3). Other suitable coating materials are calcium pectate.
nate) (Rubenstein et al., Pharm. Res., 10, 258, (1993)), colonic bacterial enzyme (c
pectin-polysaccharide (pect), which is totally degraded by olonic bacterial enzymes
in-a polysaccharide) (Ashford et al., Br. Pharm. Conference, 1992 Abstr
act 13), chondroitin sulphate (Rubenstein et al., Pha
rm. Res. 9, 276, 1992), dextran hydrogels (Hovgaa
rd and Brondsted, 3rd Eur. Symp. Control. Drug Del., Abstract Book, 1994
, 87), for example, modified guar gum such as borax modified guar gum (Rubenstein and Gliko-Kabir, STP Pharma
Sciences 5, 41 (1995)), p-cyclodextrin (Sie ke et al., Eur. J. Pharm. Biopharm, 40 (suppl), 335 (1994)), for example, cellobiose. , Lactulose, raffinose,
Saccharides containing polymers containing methacrylic polymers covalently linked to oligosaccharides such as stachyose, such as cross-linked chondroitin sulfate and calcium pectate (cal
saccharides containing natural polymers containing modified mucopolysaccharides such as metal pectin salts such as cium pectate (Sintov and Rubenstein; PCT / US91 / 03014), methacrylate galactoate Manganese (galactomannan) (Lehmann and Dreher, Proc. Int. Int.
Symp. Control. Rel. Bioact. Mater. 18, 331 (1991)), pH-sensitive hydrogels (Kopecek et al., J. Control. Rel. 19, 121 (199).
2)), such as vitreous amylose, resistant starch that is not enzymatically degraded in the upper gastrointestinal tract but is enzymatically degraded in the colon.
s) (Allwood et al., WO-89 / 11269, 1989).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/717 A61K 31/717 31/722 31/722 33/06 33/06 33/08 33/08 47 / 32 47/32 A61P 1/00 A61P 1/00 3/04 3/04 3/06 3/06 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, B , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG , SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant WEST PHARMACEUTICAL SERVICES DRUG DELIVERY & CLINICAL RESE ARCH CENTRE LIMITED WHATS PETER JAMES England 26 DG, Nottingham, West Bridgeford, 47 Haifi Lord Road, Flat 2 (72) Inventor Davis Stanley Stewart Eng 71 England, Nottingham, The Park, 19 Cavendish Crescent North F Term (Reference) 4B018 LE01 MD02 MD04 MD35 MD41 ME01 MF08 4C076 AA29 AA36 AA60 AA95 BB21 BB29 CC21 EE12J EE32 EE38 EE42 EE51 FF25 FF31 FF63 4C084 AA17 MA05 NA14 ZA701 ZC351 ZC352 4C086 AA01 AA02 EA20 EA23 HA04 HA05 HA18 HA23 MA02 MA03 MA35 MA35 MA37 MA37 MA35 MA35 MA37 MAZA

Claims (27)

[Claims] 1. A composition comprising an oil-absorption reagent, said composition being suitable for delivering said oil-absorption reagent to the small or large intestine of a mammal. 2. A composition according to claim 1, which is suitable for providing release of the oil-absorbing reagent in the colonic region of the large intestine. 3. A composition according to claim 1 which is suitable for providing release of the oil absorbing reagent in the terminal ileum of the small intestine. 4. An oil absorption delivery system having an oil absorption reagent, said system being suitable for delivering said oil absorption reagent to the small or large intestine of a mammal. 5. A form of said tablet having a core having said oil-absorbing reagent and an outer coating or layer covering said core and having a substance which prevents the release of said oil-absorbing reagent until the tablet reaches the small intestine or the large intestine. The system of claim 4, wherein 6. A caging surrounding the compartment containing the oil absorbing reagent, and a protective coating or layer on the outer surface of the caging having a substance that prevents release of the oil absorbing reagent until the capsule reaches the small intestine or the large intestine. The system according to claim 4, which is in the form of the capsule. 7. The system of claim 6, wherein the capsule has a gelatin, starch or hydroxypropyl cellulose caging. 8. The system of claim 7, wherein the capsule is a starch capsule. 9. The coating is suitable to prevent release of the oil-absorbing reagent until the system reaches the terminal ileum or colon region.
The system according to any one of the above. 10. The system according to claim 5, wherein the coating comprises an enteric substance. 11. The enteric substance dissolves only at a pH of 4.5 or higher.
0 described system. 12. The system according to claim 10, wherein the enteric substance is a polymer. 13. The system of claim 12, wherein the polymer is a methacrylate polymer with methyl methacrylate residue. 14. The system of claim 13, wherein the methacrylate polymer is a copolymer of methyl methacrylate and methacrylic acid. 15. The system of any of claims 5-9, wherein the coating comprises a material that degrades under reducing conditions. 16. The system of claim 15, wherein the substance is a polymer containing azo or disulfide groups that is preferentially degraded in the colon environment. 17. The system according to claim 4, wherein the oil absorbing reagent is any one of microcrystalline chitosan, dried aluminum hydroxide gel, microcrystalline cellulose, and calcium silicate. 18. The system of claim 17, wherein the oil absorbing reagent is calcium silicate. 19. The system of claim 17, wherein the oil absorbing reagent is microcrystalline chitosan. 20. The system of any of claims 4-16, wherein the oil absorbing reagent absorbs from 1 to 20 milliliters per gram. 21. The composition according to claim 1, further comprising a drug that suppresses enzymatic conversion of fat or another block and ingestion of fat from the gastrointestinal tract. 22. The system according to claim 4, further comprising a drug that suppresses enzymatic conversion of fat or another block and ingestion of fat from the gastrointestinal tract. 23. A method for adsorbing undigested and indigestible fat from the small intestine or large intestine of a mammal, the method comprising administering the composition according to any one of claims 1 to 3 to the mammal. 24. A method for adsorbing undigested and indigestible fat from the small intestine or large intestine of a mammal, the method comprising administering the system according to any one of claims 4 to 20 to the mammal. 25. The method of claim 23 or 24, wherein a drug that inhibits the enzymatic conversion of fat or another block and the uptake of fat from the gastrointestinal tract is administered concurrently with the system or composition. 26. Use of the oil absorbing reagent in the manufacture of a composition suitable for delivering the oil absorbing reagent to the small or large intestine of a mammal. 27. Use of an oil absorption reagent in the manufacture of an oil absorption delivery system suitable for delivering the oil absorption reagent to the small or large intestine of a mammal.