WO1989007455A1

WO1989007455A1 - Crosslinked hydrophilic copolymer for medical and paramedical use

Info

Publication number: WO1989007455A1
Application number: PCT/EP1989/000118
Authority: WO
Inventors: Brigitte De Zaepffel
Original assignee: Zaepffel Brigitte
Priority date: 1988-02-12
Filing date: 1989-02-09
Publication date: 1989-08-24
Also published as: EP0354948A1; AU3049489A; JPH02503205A

Abstract

A product for medical and paramedical use, i. e. for veterinary, surgical, and dietetic use, for curative use or for use as survival rations, consists essentially of a crosslinked alkaline hydrophilic copolymer of elementary motifs (I), where R1, R2, R3, R'1, R'2, R'3, which may be identical or different, are hydrogen atoms or C1-C3 alkyl groups, Me denotes an alkali metal and Z denotes OH or the CONH2 group. The product is preferably a hydrophilic copolymer of the acrylamide/acrylate or vinyl alcohol/crosslinked alkaline acrylate type, i. e., where R1 = R2 = R3 = R'1 = R'2 = R'3 = H, Me = Na and Z = OH or CONH2.

Description

Crosslinked hydrophilic copolymer for medical and paramedical use.

The present invention relates to a product for medical and paramedical use, it being understood that these terms must be taken in their broadest acceptations. By "medical use", we will also mean "veterinary use" and "surgical use", while by "paramedical use", we will also mean "care uses", "dietetic uses", as well as uses "as of survival ration ".

The product defined above consists essentially of a hydrophilic copolymer of the acrylamide / crosslinked alkaline acrylate or vinyl alcohol / crosslinked alkaline acrylate type and the invention will be described below with reference more particularly and respectively to the acrylamide copolymers and sodium acrylate, and vinyl alcohol and sodium acrylate, which are the preferred products.

Copolymers of crosslinked acrylamide and sodium acrylate are well known for their use in fields as diverse as in agriculture and in the adhesives and powders industry used in color reprography. It must be said that they have the property of gelling in aqueous media and of absorbing, depending on the particle size of the powders in the form of which they are present, several hundred times their own volume of water. All the big names in medical chemistry and others are associated with this kind of copolymers, for example Hoechst, Minesota Mining, Du Pont De Nemours, Eastman Kodak, Hitachi, Suminomo Chemical, Fuj i Photo, Ricoh, Toray Industries, Yasua. ..

The present invention relates to uses of such a product in a very different technical field, since it concerns the medical and paramedical fields in the broad sense indicated above. It has been found in fact that the copolymers have, vis-à-vis the human and animal organism, properties of "neutrality" which allow them this kind of applications.

The invention therefore relates to a product for medical and paramedical use, characterized in that it consists essentially of a crosslinked alkaline hydrophilic copolymer, of the following basic units:

where R ₁ , R ₂ , R ₃ , R ' ₁ , R' ₂ , R ' ₃ which may be the same or different are hydrogen atoms or C ₁ -C ₃ alkyl groups, Me represents an alkali metal and Z represents OH or the CONH ₂ group.

Preferred products among the range indicated above are those where R ₁ = R ₂ = R ₃ = R ' ₁ = R' ₂ = R ' ₃ = H, Me = Na and Z = CONH _2, that is to say say the copolymers of acrylamide and sodium acrylate proper as follows:

or where R ₁ = R ₂ = R ₃ = R ' ₁ = R' ₂ = R ' ₃ = H, Me = Na and Z = OH, i.e. the copolymers of vinyl alcohol and sodium acylate proper, as follows:

This product can be reduced to powder, advantageously having an average particle diameter of between 50 and 700 μm, preferably around 250 μm, in the dry state. In this form, it gels in the presence of any aqueous (water, serum, etc.) or hydroalcoholic medium, absorbing between 500 and 700 times its volume.

of water. The gelation process is relatively quick, since it takes between 0.5 and 5 minutes to acquire maximum and final swelling in an aqueous medium. Soaked, the powder has an average particle diameter of between 450 and 6200 μ m, preferably around 3000 μ m.

This powder is completely harmless vis-à-vis higher beings, especially mammals and humans. We actually measured a lethal dose 50 in mice and rats over 10 kg / kg body! No irritation effect could be demonstrated on intact and abraded skin in the rabbit after 24 hours, or in humans; no eye irritation in rabbits; no irritation of the vaginal membrane in the dog; no hemolytic effect on erythrocytes in rabbits, dogs and humans and no antigenic effect in dogs. Other tests will be described in the examples.

The products therefore authorize the various uses listed above.

A first use which will be described later in more detail is likely to interest dietitians, since it aims to combat bulimia and obesity, for example by means of dieting. Indeed, the product according to the invention, preferably packaged in the form of capsules, can be absorbed orally and will swell in the stomach by filling it and cutting the feeling of hunger. As will be seen later and as will be described in detail in the examples, the product according to the invention is not absorbed by the organism and is therefore completely neutral with respect thereto. Once its function is fulfilled, which is to suppress hunger by saturating the stomach, it progresses as it is and without any transformation in the intestine to be evacuated by natural routes. We can note in some cases a very slight laxative effect, which is rather a favorable element for the type of use mentioned above. It can therefore be incorporated into a weight loss diet, where it replaces a large part of food by correspondingly reducing their intake in terms of calories or nutrients.

In such uses, the product according to the invention is ingested as it is, without other excipients than those necessary for the form of packaging or for the galenic form considered.

Another use consists in fixing on the product according to the invention, in calculated quantity, the nutrients (proteins, lipids, carbohydrates, vitamins, mineral salts, trace elements, etc.) necessary for the human organism, in order to constitute more appetizing survival rations than a concentrate or pills, while having the advantage, as above, of cutting the feeling of hunger dictated by the stomach.

Another important area of use of the product according to the invention is that of care. Thus, in the field of hygiene or simply comfort care, the product according to the invention can be packaged, in an appropriate form, in a woven or nonwoven envelope according to the type of application and be used for its properties. of absorption as dressings and compresses, taking advantage of its very great ability to absorb liquids. In the same way, we can make mattress covers, or diapers for babies or adults with incontinence. It can also be packaged, in an appropriate form, as sanitary napkins or tampons where its absorbent properties will be highly appreciated. In the field of medical care, whether or not impregnated with an active principle having curative or healing properties and housed in an appropriate envelope, it can be used as a surgical compress or dry or wet plaster.

In the strictly medical field, which is therefore of interest to allopaths as long as homeopaths, the product according to the invention can be impregnated with an active principle and be deposited on the surface of the organism or be transported inside it. . Ingested orally, it can be used as a gastric dressing to protect the intestinal mucosa and to treat, calm pain in gatrites, esophagitis, gastrointestinal ulcers, colitis, polyposis, polyps, etc.

In this same medical field, the product according to the invention impregnated with an active principle can be used for an internal topical application, the copolymers protecting the active principle from too rapid degradation and therefore making it possible to send it to the site where he must act.

Externally, the product according to the invention impregnated with an active principle can be applied locally, either by injection, or directly on the skin where the latter will act in the manner of a transdermal.

We can also consider the use in oncology, internally or externally, the product according to the invention being in charge of an active principle (chemotherapy) or a radio-element (radiotherapy).

Another important use, where the product is used in the presence of liquid, at the start of its gelification, is in the field of surgery, in particular plastic surgery. Indeed, after gelation, the product according to the invention constitutes an excellent maintenance or filling substance, inert with respect to the organism and in practice non-biodegradable. It will then be used by injection or by incision for the treatment of wrinkles for example, breast ptosis or as prosthesis or plasty, testicles, etc.

The invention will be better understood with reference to the examples below, given without limitation. These examples demonstrate the harmlessness of the product according to the invention and, consequently, its great employability in the fields mentioned above, in particular, in dietetics and in the field of care.

Example 1

Digestive elimination

Due to the size of the swollen particles of water, there is little chance that they can cross the barrier of the intestinal wall.

To verify this, five patients received for three days a daily dose of 10.0 g of pre-swollen ®IGETAGEL copolymer in two doses, in 250 ml of mineral water. This copolymer is available from OMAREX in Schlieren ZH, Switzerland.

From the first day, the stool was collected for five days. They were washed and sieved through a filter with a porosity of 500 m. The collected material was collected and weighed at the end of the observation period. The recovered weight is as follows for the five subjects:

1. 24.6 g 2. 26.3 g 3. 28.2 g 4. 25.1 g 5. 27.2 g

The average recovery value is 26.88 g which, taking into account losses due to handling, represents an almost total elimination of the product.

In addition, on microscopic examination of particles, the shape and structure do not appear different from what they were at the start. The digestive path of particles does not change their nature and structure.

Example 2

Study of the susceptibility of the copolymer to enzymes

Samples of particles of the copolymer were placed in the presence of water to obtain maximum swelling. The gel was dispersed with a Vortex and a suspension of 50,000 particles / ml was prepared. A sample of this suspension was put in the presence of the following enzymes: - Amylase 10, 50, 100 meg / ml

- Trypsin 10, 50, 100 meg / ml

- Pepsin 10, 50, 100 meg / ml

The suspensions were incubated for four hours in an incubator at 37 ° C. After incubation, the cells were counted. The number of cells recovered is of the same order of magnitude as the entire initial sample (between 49,250 and 50015). Furthermore, the weight after centrifugation is the same as that observed at the start of the experiment.

The copolymer particles, swollen with water do not seem to be attacked by the enzymes used. This result confirms the results concerning elimination by the digestive tract.

Example 3

Allergenicity study

The aim of this study is to determine the allergenic potential of the copolymer particles. To do this, a dose of twice 2.0 g / day, in the presence of water, is administered for 5 days to 20 volunteers.

Before the start of the test and four days after the end of the test, the following tests were carried out:

1. A prick test with the swollen substance, with reading of the skin response after twenty minutes and two hours (immediate hypersensitivity).

2. A patch test with the swollen substance with reading after 24 and 48 hours (cell-mediated hypersensitivity).

In all subjects, both immediate and late tests remained negative. The copolymer therefore appears to be immunologically inert.

3 of the 20 subjects introduced into the study complained of a certain gastric heaviness for one to two hours after taking the copolymer. There were, however, no complaints of gastric or enteric colic pain. Finally, a slight laxative effect was noted by all subjects.

It should be noted that such effects, if they were systematically verified on a large number of subjects, are not negative, quite the contrary, within the framework of a dietary application of weight loss. The physiological sensation of hunger is erased and the intestinal transit is facilitated.

Example 4

Study of cellular behavior in vitro

The behavior of the immunocompetent and phagocytic cells with respect to the copolymer particles is analyzed. Insofar as some small particles could possibly cross the intestinal wall, it is useful to know their fate and their effects on immune functions.

a) Cytotoxicity test

Increasing concentrations of swollen particles (from 20,000 to 200,000) have been brought into contact with a constant population of lymphomonocytes from allergic patients. Incubation was carried out in RPMI medium in the presence of 10% of AB ° human serum. It was four hours. The cells were then placed ¹ in the presence of Trypan blue and within 10 minutes of contacting, the number of viable cells was determined.

The results are as follows, in average value of ten samples

% of viable cells

Control 93% S. 20,000 95% S. 100,000 88% S. 200,000 92%

b) Lymphocyte stimulation test

Ten cultures of lymphomonocytes were practiced, the cells coming from allergic subjects.

A five-day incubation was carried out in RPMI medium plus 15% AB serum. The cultures consisted of:

- 1 control batch (phytohemaglutinin) stim. lymph. T

- 1 batch with mitogin PHA (lectins, vegetable megin)

- 1 batch with Con-A (concavaline A) stim. lymph. B

Three parallel batches were cultivated with, however, in addition 50,000 particles of swollen copolymer / ml of medium. After incorporation of ³ H-Thymidine (1.0 uc / 10 ⁶ cells) the cells are washed and the isotopic activity estimated in a liquid scintillation counter (Beckmann). The results are expressed in one stroke per minute (cpm).

The results obtained are as follows:

Cpm ± SE

1. Control 369 ± 17

1a. Control + particles 375 ± 21

2. PHA 76 593 ± 7 250 2a. PHA + particles 74 781 ± 5 720

3. Con-A 28 513 ± 1 780 3a. Con-A + particles 29,557 ± 2,046

Statistical analysis (+ student test) shows no statistically significant difference between, respectively 1 and 1a; 2 and 2a; 3 and 3a.

In conclusion, at the concentration used, the copolymer particles do not interfere with lymphomonocyte proliferation in vitro. c) Phagocytosis test

Polynuclear cells from allergic patients isolated on Ficoll-Isopaque gradients were washed and in RPMI medium brought into contact with copolymer particles. The cell / particle ratio was 1/5. Fifteen experiments were carried out. The cell suspension was incubated for two hours at 37 ° C. The separation of the cell / particle pair was made by sedimentation in a hypotonic aqueous medium.

In each test, five hundred poly-nuclear cells were counted and the presence of intracellular particles determined.

No particle phygocytosis has been observed. Indeed, the swollen particles are so much larger than the cells that phagocytosis is hardly possible. On the other hand, rosette forms have been noted, that is to say eight polynuclear cells attached to the periphery of a particle probably in an attempt at phygocytosis.

An identical test was developed this time using monocytes isolated on a glass plate. Here also, no phygocytosis was observed, but some rosettes of the same type as those observed with polynuclear cells. The phagocytic, polynuclear and monocyte cells are not able to phagocyte the vinyl / acrylic particles.

Example 5

Compresses

40 × 40 cm x 4 mm thick compresses are prepared by enclosing balls of the © IGETAGEL brand copolymer sold by OMAREX in a non-woven envelope, which, in turn, may in turn be covered with a gauze. traditional. These compresses are applied to wounds where their absorbent properties work wonders compared to traditional compresses. In addition, they are a remarkable barrier against infection of wounds by germs from the outside.

Claims

1. Product for medical and paramedical use, characterized in that it consists essentially of a crosslinked alkaline hydrophilic copolymer, of the following basic units:

where R ₁ , R ₂ 'R ₃ ' R ' ₁ , R' ₂ , R ' ₃ which may be the same or different are hydrogen atoms or C ₁ -C ₃ alkyl groups, and Me represents an alkali metal and Z represents OH or the group CONH ₂ .

2. Product according to claim 1, characterized in that the crosslinked hydrophilic copolymer is a copolymer of acrylamide and sodium acrylate where Z = CONH ₂ as follows:

3. Product according to claim 1, characterized in that the crosslinked hydrophilic copolymer is a copolymer of vinyl alcohol and sodium acrylate where Z = OH, as follows:

4. Product according to claims 1, 2 or 3, characterized in that the crosslinked hydrophilic copolymer is in the form of a powder whose average particle diameter is between 50 and 700 μm, in the dry state.

5. Product according to claims 2 or 3, characterized in that the hydrophilic crosslinked copolymer gels in aqueous media by absorbing between 500 and 700 times its volume of water.

6. Salt product has claim 1 for dietary use for the treatment of obesity and bulimia or in weight loss diets, characterized in that it is absorbed orally.

7. Product according to claim 6, characterized in that it is packaged in capsules.

8. Product according to claim 1 for use as a survival ration, characterized in that it contains nutrients and is absorbed orally.

9. Product according to claim 1 for care use, characterized in that it is formed in sheets, layers, towels, tampons, dressings and compresses inside a woven or nonwoven envelope.

10. Product according to claim 9, characterized in that it contains an active principle with curative or healing effect.

11. Product according to claim 1 for medical or veterinary use, characterized in that it contains an active principle.

12. Product according to claim 11, characterized in that it is packaged for an extra topical or intra-corporal application.

13. Product according to claim 1 for surgical use as a support or filling substance, characterized in that it is applied in the presence of an aqueous medium, at the start of gelation.