EP0861083A1

EP0861083A1 - Microcellulose-based preparations

Info

Publication number: EP0861083A1
Application number: EP96939020A
Authority: EP
Inventors: Francesco Saverio Dioguardi
Original assignee: White Swan BV
Current assignee: White Swan BV
Priority date: 1995-11-14
Filing date: 1996-11-13
Publication date: 1998-09-02
Also published as: ITTO950917A1; ITTO950917A0; AU7623296A; JP2000502048A; WO1997017976A1; IT1290792B1; AR008987A1

Abstract

According to the invention, a dimensionally specific physical form of polycellobiose, also called microcrystalline cellulose or microcellulose, is vehiculated in pharmaceutical forms suitable for ingestion (such as capsules, tablets, granula or powder forms, etc.) in order to obtain a regulatory effect on gastro-intestinal transit, in all conditions where cellulose and other fibres may not be well tolerated or are contraindicated.

Description

MICROCELLULOSE-BASED PREPARATIONS

Description

All kind of therapeutic approaches to treatment of constipation have important biases peculiarly on long term treatment schedules. Diphenylmethane (phenolphtalein, pysacodil) and antraquinone containing laxatives of vegetable origin (cascara, senna, rhamnus, danthron, aloe) have been targeted as suitable only for very short period or extemporary treatment of constipation for their potential risks by government health, food and drug agencies of different countries. On the other hand, saline cathartics (magnesium, sodium phosphate and potassium salt) cannot be used chronically and are potentially dangerous because of calcium and water excessive losses, and can thus inducing malabsorption of soluble drugs and vitamins. Their use is limited also by pain as frequent collateral effect. In the last two decades, mainly as a result of epidemiologic studies on large populations, the role of fibres, the main indigestible alimentary constituent, has been focused by nutritionists. This is mainly due to their role in the possible prevention of colon carcinoma as well as to their regulatory effect on dimensions, consistence and speed of intestinal transit. For this reason, dietary fibres have found a wide application in the treatment of constipation. The term dietary fibres is referred to the total natural fibrosic contents available in aliments, mainly of vegetable origin, which cannot be chemically digested by the enzymatic system of humans. One of the nutritional problem lies in the fact that, on average, occidental diets lack a sufficient amount of fibres, due to the treatments that food undergoes during its preparatory stages (as an example, bran is removed from wheat grains when transformed in flour). According to the U.S. National Health and Nutrition

Examination Survey, the average daily fibre introduction in U.S.A. is 1 1 g/die, whereas a reasonable recommendation calls for 20-25 g/die.

Entering more into details, classification of dietary fibres is referred to the residues of indigestible vegetables and can be summarized as follows:

1. cellulose; 2. non-cellulosic fibres.

1. Cellulose

Cellulose is a polysaccharide (C₆Hιo0₅) whose molecular weight ranges from 300.000 to 500.000, formed by linear chains of D- glucose molecules linked together by beta bonds.

Alimentary fibres consist of millions of cellulose molecules linked together in chains, whose length may even reach several tens of centimeters or meters. Beta bonds are undigested by mammals^" enzymatic systems (for instance, starch has alpha bonds).

Cellulose is the main structural constituent of vegetable cell walls. It is insoluble in distilled water and acids.

2. Non-cellulosic fibres Non-cellulosic fibres consist of non-cellulosic polysaccharides comprising emicelluloses, pectines, mucillages and other media derived by algae, resins and lignin. Besides water absorption, non-cellulosic fibres have also other collateral effects due to their chelant action as they seem to be able to chelate biliary salts and cholesterol, thus reducing their absoφtion; however, this effect is unfortunately reached also with drugs and minerals, such as iron, calcium and zinc. Further, resins and soluble fibres contained therein may undergo a bacterial digestion in the colon, and elicit short-chain volatile fat acids and gas production (carbon dioxide and methane). The use of mixed alimentary fibres, either cellulosic or not, has become common use in the treatment of constipation, in the form of "bulk forming" laxatives, due to their water retention capability. The size of fibres seems to have a determining action as the longer the fibres are the bulkier will they become with fluid. As a matter of fact, the previous technique uses fibre mixtures of alimentary origin whose chain is the longest possible to maximize the "bulk forming" effect, with all the relevant implications on water retention inside and its chelating effect on various biologic molecules (specifically biliary salts and fat acids). Moreover, the phytate contents of vegetable fibres is significant during calcium and iron based treatments, where phytates have a chelating action that reduces their bioavailability substantially.

The use of methyl-cellulose is known for laxative purposes due to its specific water absoφtion and solubility properties. Methyl-cellulose and carboxymethyl-cellulose derived from it are products obtained by synthesis, which modify the chemical- physical characteristics of cellulose, i.e. from insoluble to soluble in cold water and insoluble in hot water.

Solubility is a function of the number of methylic units used as substituents; the products known on the market have a 1,8 substitution degree, i.e. they contain about 29% methossilic units. Methyl-cellulose and carboxymethyl-cellulose can be converted into gel.

Therefore, the pharmacologic laxative effect according to the known state of art can be summarized as follows:

- increase of alimentary bolus and stools,

- increase of water contents, with accelerated ileum transit,

- increased quantity in the colon of biliary salts available in the stools due to the chelating effect, - eliciting gas production and increased presence of free fat acids due to bacterial digestion of aliments escaped to digestion as they were bulk entrapped and/or of constituents of said alimentary fibres entrapped by the bacterial intestinal flora.

It is the object of the present invention to overcome the problems of the previous technique. In particular, the aim of the research leading to the identification of the present invention was to solve the limit and problems posed by actual knowledge and state of the art, by corresponding to all the following requirements:

- physical not chemical action; - emulsionant action on water-oily interfacies;

- easily controlled, dose-related osmolarity;

- bulk forming, dose related effect;

- no caloric contribution;

- indigestibility by human digestive enzymes - no chemical interaction with drugs.

These characteristics would be appropriate for an ideal regulator of intestinal motility, suitable for acute or chronic safe use. According to the present invention this object is obtained with the use of microcellulose to be vehiculated in pharmaceutical forms suitable for ingestion (tablets, capsules, granular or powder form, etc.) as the sole or main active ingredient in preparations suitable to cover either partially or totally the requirements of alimentary fibres in humans or animals, or in preparations to regulate intestinal transit, preferably suitable for the use in all conditions of altered intestinal motility due to an insufficient or viceversa excessive water retention, first in the alimentary bolus and then in stools, where microcellulose affects in a regulatory manner the solid-fluid ratio during intestinal transit.

Further objects and advantages of the present invention will be apparent from the following detailed description, which is supplied by way of an explanatory but non limiting example. Microcrystalline cellulose or microcellulose is a preparation of fragments of cellulose crystallite units in the form of a non fibrosic powder, containing particles in the form of rigid small bars, whose refraction index is 1.55.

The molecular weight of the basic component, microcellulose, can range as required from 10.000 to 300.000, i.e. between a range of numbers of atoms classified from 10⁴ to IO⁹, whose dimensions allow a liophile colloidal dispersion. Availability of different molecular weights of microcrystalline cellulose allow to graduate the number of molecule in any given unit of weight, thus to improve or reduce the osmolar effect ofthe product. Examples of how microcrystalline cellulose is synthesised are described in US Patents nos. 2,978,476 and US 3,141,875. Microcrystalline cellulose or microcellulose is featured by its peculiar property of being slightly soluble in diluted alcaline solutions, whereas it is totally insoluble in acids and does not gelify under any conditions.

Therefore, microcellulose is fully inactive in the stomach and just a light solubility can be foreseen in the continuation of the gastrointestinal transit with pH raise. Moreover, unlike methyl- cellulose, microcrystalline cellulose will not dissolve in any water volume.

Chemical-physical characteristics of microcrystalline cellulose to form a sol have provided a new indication for its use as emulsifier, foam-repellent and thickening agent.

However, it is the object of the present invention to use microcellulose to obtain a regulatory effect on intestinal motility due to its chemical-physical characteristics. This has the puφose of obviating to the problems caused by alimentary fibres available so far on the market, such as subordination to water volume, digestion of part of their constituents and often unendurable production of large intestinal gas volumes, their chelating effect con pharmaceutical products and some minerals salts. In addition, according to the present invention, microcellulose is provided for use under those conditions where alimentary fibres are not tolerated, being excessively irritant and eliciting a too fast, frequent and irritant intestinal transit of bolus volume. Microcellulose is not digested by mammals because they have no cellulase, i.e. the enzyme required to break beta bonds between D- glucose molecules. For this reason, microcellulose will not cause, as of itself, any problems related to the digestion of sugars contained in the fibres or alimentary fibres. 7

Due to the relatively small molecular size in respect to cellulosic fibres (containing milions of closely interlaced cellulose units for total macroscopic sizes), microcellulose is also featured by a lower water eagerness and unlike water soluble methyl-cellulose it is insoluble in water.

Therefore, a given quantity of microcellulose will yield a number of molecules as liophile dispersion to the water available with or contained in the aliments, as a fixed proportion of the water- microcellulose ratio (as it can be easily proved by gradually adding water volumes to a fixed cellulose volume: a progressive reduction of the precipitate will in fact show up with increasing volumes of solvents; however, it will remain a precipitate also with a 1000:1 water-cellulose weight ratio). Thus, a gradual "bulking" effect will be obtained, which is easily dosable for progressive dose increases.

Further, microcellulose will develop through its insolubility an efficient absorbing effect in all those conditions where an excessive intestinal transit speed is caused by intestinal inability to reabsorb water. This condition occurs and has a clinical significance eg. in the case of irritable colon syndrome, characterized by alternating alvus, i.e. repeated alternation of constipation and stools. Such a condition is often related to the intestine intolerance to some sugars available in the aliments that cannot be digested at all, or to an oversensitivity to vegetable long fibers, or both of them.

The patient suffers from constipation if fibres are eliminated, whereas he will suffers from diarrhea when vegetables and/or milk products are introduced. Colon irritability, in fact, is often due to a lack of intestinal lactase (i.e. the enzyme capable of separating the lactose unit in two sub-units, namely galactose and glucose). The resulting overosmolarity of the alimentary bolus would anyway lead to an intestinal bolus containing an excessive water volume, all the more if long vegetable fibres are contained therein, which have an enormous swelling capacity.

Moreover, when the bolus reaches the intestine, the intestinal bacterial flora will rapidly convert lactose into lactic acid, carbon dioxide and water, stressing both the irritant effect and transit speed, and alternating strong abdominal distention and pains. While the therapy will obviously require a reduction or removal of milk products, introduction of microcellulose according to the present invention has a regulatory effect on the bolus and makes it consistent, however it will not lead to the overdistention phenomena as caused by fibres of vegetable origin, right for the limited swelling capacity of microcellulose.

Moreover, the reduced length of the particles forming it will not lead to any overdistention phenomena due to formation of large boluses difficult to fraction and having a reduced absoφtion surface; moreover, since the precipitate-dispersion ratio of microcellulose is a function of water volume, there will be a self- regulation between the dispersed and non-dispersed part percentage, suitable to maintain the best possible solid-fluid ratio, i.e. providing a regulatory action. On the contrary, methyl -cellulose and carboxymethyl-cellulose, which are strongly soluble in water, only tend to maintain the water volume present in the intestinal lumen at a maximum level, operating solely as transit or stool bolus accelerators. Unlike alimentary fibres (bran, mucillages, etc.), microcellulose does not contain any constituents capable of a further incentive for bacterial degradation with gas production.

Microcrystalline cellulose is a polyhydroxyaldheide, thus it has a slight polarity between the terminal portion which is lyophilic and the initial portion which is hydrophilic. In our experiments this characteristic of the molecule allows either an important and irreversible dispersion of oil in water media, or a reduction in capillary water pressures. Thus, reducing the size of oil drops in food introduced by diet and water adhesiveness, the introduction of sufficient amounts of microcrystalline cellulose would improve also gastric emptying. This phenomenon has never been described before. On the contrary, all alimentary fibers are well known and clinically used for the puφose to slow gastric emptying, bloating being the subjective consequence which very frequently leeds to discontinuation of fibers introduction.

Therefore, according to the present invention, microcellulose vehiculated in pharmaceutical forms for ingestion (tablets, capsules or granular and/or powder form) is indicated as the main or sole active constituent in preparations for use in all conditions of altered intestinal motility due to insufficient or viceversa excessive water presence, first in the alimentary bolus and then in stools. Due to its insoluble characteristics (unlike soluble methyl-cellulose and carboxymethyl-cellulose) that make it an ideal lyophilic colloid, microcellulose develops a regulatory effect on the solid-fluid ratio during intestinal transit. It is apparent how according to the present invention microcellulose is indicated for use as the main or sole active ingredient in preparations adequately covering either partially or totally the requirements of undigested fibres in the alimentary diet of humans and animals. Therefore, in this frame microcellulose can be used as an ideal dietetic integrator in all pathologic conditions where fibres assumption is contraindicated since irritation is caused by an excessive length of fibres. Likewise, microcellulose according to the present invention is indicated as an ideal dietetic integrator in all conditions where the intestinal assumption of fibres should be maintained or increased, but this is contraindicated because of the risk of malabsoφtion induced by them on calcium and iron (eg. osteoporosis, pregnancy, sideropoor anaemia, etc.). According to the above description the characteristics of the present invention will be apparent, as it is obvious also for its advantages. Specifically, as described above it will be apparent how microcellulose is an ideal integrator of undigested fibres for its dimensional, chemical-physical and organolectic characteristics, having an ideal regulatory effect in all conditions of decreased intestinal motility and above all in all conditions where other undigested fibrous residues are not tolerated and even contraindicated for therapeutic puφoses. Finally, microcellulose can also be used as a constituent for association with other molecules, to modulate the preponderant effect of some substances (eg. a strong hydrophilous effect of methyl-cellulose and psyllium) or stress the reducing tensio-active effect of other substances (eg. symeticone).

Claims

1. The use of microcellulose, to be vehiculated in pharmaceutical forms suitable for ingestion (tablets, capsules, granular and powder form, etc.) as the sole or main active ingredient in preparations suitable to cover either partially or totally the requirements of undigested fibres in the diet of humans or animals.

2. The use of microcellulose according to Claim 1 in preparations suitable to act as a dietetic integrator in all pathologic conditions, where fibres assumption is contraindicated due to irritation caused by an excessive fibre size.

3. The use of microcellulose according to Claim 1 in preparations suitable to act as a dietetic integrator in all pathologic conditions, where the intestinal assumption of fibres should be maintained or increased, but is contraindicated because of the risk of malabsoφtion induced by them on calcium and iron (eg. osteoporosis, pregnancy, sideropoor anaemia, etc.).

4. The use of microcellulose according to Claim 1 in preparations having a regulatory effect on the solid-fluid ratio during intestinal transit, in all pathologic conditions of altered intestinal motility due to insufficient or viceversa excessive water presence first in the alimentary bolus and then in stools.

5. The use of microcellulose according to one or more of the above Claims, for association with other molecules to modulate their preponderant effect or stress the reducing tensio-active effect of other substances.

6. Preparations having a regulatory effect on intestinal transit, in particular suitable for use in all conditions of altered intestinal motility due to insufficient or viceversa excessive water presence, first in the alimentary bolus and then in stools, characterized in that they comprise microcellulose in pharmaceutical form suitable for ingestion (tablets, capsules, granular and powder form), as the sole or main active ingredient having a regulatory effect on the solid- fluid ratio during intestinal transit.

7. Preparations suitable to cover either partially or totally the requirements of undigested fibres in the diet of humans or animals, characterized in that they comprise microcellulose in pharmaceutical forms suitable for ingestion (tablets, capsules, granular and powder form) as the sole or main active ingredient.

8. Preparations comprising microcellulose according to the above description and for the puφoses as specified.