NL8303314A - Medicaments for rectal or vaginal admin. - based on non-spreading hydrophilic hydrogel carrier - Google Patents

Abstract

Medicaments contain one or more active ingredients distributed in a base material comprising a non-spreading hydrophilic hydrogel (I). (I) is pref. a crosslinked polyhydroxyethyl methacrylate produced by polymerising hydroxyethyl methacrylate (HEMA) in the presence of azobisisobutyronitrile (ABIBN) as initiator and ethylene glycol dimethacrylage (EGDM) as crosslinker. The amt. of crosslinked used is up to 15 wt.%, esp. 0-2.5% for fast release or 2.5-15% for slow release.

Description

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Medicines for administration by the rectal and vaginal routes.

The invention relates to medicaments which are intended for administration by rectal and / or vaginal route and which comprise one or more active substances divided into a base is material. In particular, the invention relates to medicaments whose active substance is rapidly degraded, inactivated or excreted by the liver.

Although administration of drugs by the oral route is in most cases the easiest and most convenient for the physician and patient, administration by this route does not always lead to optimal results. Many active substances in medicines can be completely or partially broken down by gastric juice and / or intestinal bacteria; various active substances are poorly absorbed through the gastrointestinal tract and the material absorbed through the intestine passes through the portal vein into the liver before it can exert its activity at the target site in the patient's body. A large number of medicinal compounds are rapidly degraded or otherwise inactivated in this liver, so that only a fraction of the ingested material actually benefits the patient.

To overcome these drawbacks associated with the administration of drugs by the oral route, other modes and forms of administration have long been used, eg creams and ointments for topical administration, injectable fluids and suppositories, respectively, vaginally bullets (ovula) for administration by rectal and vaginal routes, respectively. Topical preparations 25 are used practically only for a topical effect and injection fluids must be prepared in a very pure, sterile and pyrogen-free manner and in most cases administered by a physician or nursing staff.

For rectal and vaginal preparations, the active substance cannot be introduced as such into the rectum or vagina.

This active substance is therefore homogeneously distributed in a base material, which is then processed into smaller units (suppositories or vaginal balls). As a basic material, most fats (cocoa butter) or hydrophilic compounds (polyethylene glycol derivatives) i v -j ΰ l <t rv -¾ -2- are used. Both basic materials have their specific drawbacks for different applications, which are mainly based on the partition coefficient of the active substance between the base material and the mucous membranes of the rectum, while they have the common objection that they are spread over a large spread surface. The latter means that a large percentage of the active substance is not absorbed or absorbed at the insertion site, at the bottom of the rectum, but in the upper part of the rectum. This upper part of the rectum is flowed through the portal vein system, so that active substance absorbed there is first transported through the liver before it benefits the body. This is often accompanied by large losses from decomposition or inactivation. The blood from the lower part of the rectum is drained into the general circulation by another blood vessel system without liver passage. Although this has been known for a long time, this has never been taken into account in the preparation of suppositories and vaginal balls.

Furthermore, it is desirable for many types of medicinal compounds to be supplied to a greater or lesser extent. However, to date, no rectal or vaginal administration forms have been proposed with which the delivery pattern can be accurately adjusted, eg a zero-order delivery pattern (constant release, i.e. the amount of active agent released does not change with time).

The invention now provides drugs of the type mentioned in the preamble, which do not have the above-mentioned drawbacks and are characterized in that this base material consists wholly or partly of a non-spreading, to a greater or lesser extent hydrophilic hydrogel.

Hydrogel and are water-insoluble, more or less hydrophilic, usually cross-linked systems capable of absorbing or containing a varying amount of water. Examples are dextrans; collages, e.g. gelatin; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hydroxyethylmethyl-35 cellulose; acrylonitrile; acrylamide; (poly) vinyl alcohol; (poly) N-vinyl pyrrolidone; ethylene vinyl acetate; vinyl acetate; (co) polymers of 8303314 - * ........

-3- methacrylic acid, ethyl methacryl! aate and methyl methacrylate; positively or negatively charged poly (electrolyte) complexes; hydroxy acrylates and hydroxymethacrylates, such as hydroxyethyl methacrylate, methoxyethyl methacrylate, methoxyethoxyethyl methacrylate, methoxydiethoxyethyl methacrylethyl acrylate, methyl ethyl acrylate, hydroxyethyl acrylate, hydroxyethyl, methyl ethyl acrylate, methyl ethyl acrylate, methyl ethyl acrylate, methyl ethyl acrylate, methyl ethyl acrylate, methyl ethyl acrylate,

Very suitable appeared cross-linked polyhydroxyethyl methacrylate. A very suitable crosslinker is ethylene glycol dimethacrylate.

Hydrogel and swell on contact with water by absorbing a varying amount of water, but do not dissolve, nor do they spread over the wall of the rectum or vagina. Partly because of this swelling, an active substance distributed in this basic material can be gradually released into the surrounding tissue of the patient, after which it can be absorbed or absorbed. This avoids a shock dose of the active substance, guarantees a long-term supply of the patient with the medicinal substance and prevents a rapid conversion or inactivation thereof by the liver.

The following advantages are associated with the use according to the invention of a non-dispersible, water-insoluble, but water-swellable hydrogel. First of all, the absorption of the active substance can be significantly limited to a certain area of the rectum or vagina, in particular the last part of the rectum, which can significantly prevent liver passage, which is especially important for active substances that would be rapidly converted or inactivated when passed through the liver.

In order to properly control dissemination in the rectum or vagina, the rate at which the active substance is released by the hydrogel must be less than the rate at which that active substance is absorbed by the rectum or vagina surface. Furthermore, the invention allows the rate of delivery and the rate of delivery (time course of delivery) to be adjusted as needed. In particular, by a suitable choice of the hydrogel material (composition, amount of crosslinker, polymerization conditions), a constant release can be realized, which is desirable for many substances and also promotes that »« r * f f ö w <* / i Λ

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-4- the active substance is absorbed at the desired location.

The hydrogels according to the invention can be obtained in a simple manner by a polymerization of corresponding vinyl monomers. This polymerization is usually carried out in a manner customary for this type of vinyl monomers. A peroxide compound or a radical former such as azo-bis-isobutyric nitrile can be used as the catalyst. Depending on whether a rapid or slow release of the active agent to the patient's body is envisaged, no, little, or quite a lot of a cross-linking agent is polymerized during this polymerization. A good cross-linking agent for hydroxyethyl methacrylate has been found to be ethylene glycol dimethacrylate. This can be applied in percentages of 0-15% based on the final polymer. Although at a crosslinker content of about 9.5% the release rate usually reaches a minimum, depending on the desired release rate, usually no more than 4% of this crosslinker is used. The boundary between relatively still fast and slow releasing hydrogels is approximately 2.5% crosslinker for polyhydroxyethyl methacrylate.

Also, the release rate of the actives 20 can be controlled by using the water content of the hydrogel and applying a coating thereon. At a low water content of the polymer (for hydroxyethyl methacrylate <20%), the release is delayed; at a high water content (for hydroxyethyl methacrylate> 40>) accelerated. In order not to introduce foreign substances, it is easy to coat with the monomer with a higher percentage of crosslinker, followed by a separate polymerization thereof.

For the manufacture of the finished dosage forms, the active substance or combination of active substances must be homogeneously distributed in the base material. Preferably, for this purpose a mixture of active substance or substances is mixed and polymerized with the starting materials required for the hydrogel in liquid form. Of course, the polymerization conditions must not adversely affect the active substances, while in addition a homogeneous distribution of the active substance or substances must be ensured by the base material. It is also possible to have the active substance or substances in solution taken up by the polymer after the polymerization.

8303314 -5- v 5 '

In principle, any active substance or combination of active substances can be processed into the present administration form and administered in this form. The present form is particularly advantageous for active substances which are rapidly broken down or inactivated by the liver, because after administration in the present form they are certainly partly absorbed without passing through the liver and thus benefit the patient in a higher percentage. The following are some examples of categories of drugs that can be administered rectally: 10 a) Anti-epileptics, such as diazepam; b) Analgesics and anti-inflammatory agents, which often irritate the stomach and small intestine; c) Hypnotics and sedatives, to prevent overdoses and attempted suicide; D) Theophylline derivatives for the prevention of nighttime asthma attacks; e) The following compounds rapidly inactivated and / or excreted by the liver: lidocaine, propranolol, alprenolol, pindolol, metoprolol, imipramine, dopamine, nortryptyline, seroto-20 nine, methyl testosterone, chloromethiazole, hydralazine, acetylsalycic acid, glycerol trinitrate, isoprenaline, L-dopa, debrisoquine, dexamethasone, estrogens, methyl-dopa, terbutaline, chlorpromazine, hydrocortisone, cortisone, aldosterone, progesterone, isoniazid, morphine, pentazocine, oxymorphine, pethidine, propoxyphen, buprenorphorphoromorph.

Naturally, the above list does not claim to be complete. Thus, the invention is not limited to drugs containing one or more of these active substances.

The invention is further elucidated by means of a few examples.

Example I

This example concerns the in vitro and in vivo release model of a hydrogel incorporating antipyrine as the active substance.

The composition subjected to polymerization was: HEMA ^ 55% EGDMA2 ^ 0.55% 83 0 33 14 r, -6-H2 O 15% antipyrine 29.45% 1) ΉΕΜΑ represents hydroxyethyl methacrylate 2) 5 ' EGDMA stands for ethylene glycol dimethacrylate

As the initiator, 1 mg of azo-bis-isobutyric nitrile per ml of the mixture was used. The polymerization reaction was carried out at 70 ° C for 12 hours.

The release pattern was determined for cylindrical preparations 30 mm in length and 9.4 mm in diameter.

In vitro release was examined in 100 ml physiological glucose.

In vivo release was examined in two healthy male volunteers. Administration was rectal.

The results are shown in Fig. 1, in which the cumulative antipyrine release is plotted against time.

Example II

This example concerns the in vitro and in vivo release model of a hydrogel incorporating lidocaine HCl as the active substance. The polymerized composition was: HEMA 53.7% EGOMA 1.3% 25 H 2 O 35% lidocaine HCl 10%

The polymerization was carried out analogously to Example !.

Cylindrical preparations 10 mm in length and 4 mm in diameter were used to determine the release pattern.

The in vitro study was carried out analogously to Example 1. The in vivo study was performed on rats where administration was by rectal route.

The in vitro release is shown in Fig. 2, while FIG. 3 shows the result of the in vivo study; in fig. 3, the lidocaine concentration in the blood is plotted against time, 8303314 -7-

As shown in Fig. As it turns out, the lidocaine is also released here in the course of 3 hours. The area under the curve, which is a measure of the amount of the active substance reaching the general circulation, shows, when compared to rectal administration by means of a classical suppository, that about 11 times as much lidocaine reaches the general circulation. This demonstrates that administration by means of the non-disintegrating, non-spreading hydrogel according to the invention can effectively avoid passage through the liver and associated degradation of the active substance.

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Claims (8)

1. Medicines intended for administration by rectal and / or vaginal route and. comprising one or more active substances divided into a base material, characterized in that this base material consists wholly or partly of a non-spreading, to a greater or lesser extent, hydrophilic hydrogel. Medicaments according to claim 1, characterized in that the hydrogel is a cross-linked poly-hydroxyethyl methacrylate. Medicaments according to claim 1 or 2, characterized in that the base material was prepared by polymerizing the monomer, such as hydroxyethyl methacrylate, using azo-bis (isobutyric nitrile) as a catalyst or initiator. Medicaments according to one or more of claims 1 to 3, characterized in that the base material is polymerized using at most 15¾ of a crosslinking agent, based on the weight of the finished polymer. Medicaments according to claim 4, characterized in that the base material, consisting of polyhydroxyethyl methacrylate, was prepared for a relatively rapid release of the active substance using 0-2.5¾ crosslinking agent. Medicaments according to claim 4, characterized in that the base material, consisting of polyhydroxyethyl methacrylate, was prepared for a markedly slow release of the active substance using more than 2.5 crosslinking agent. Medicaments according to claims 4-6, characterized in that the cross-linking agent used is ethylene glycol dimethacrylate, 8303314-9. Medicaments according to one or more of Claims 1 to 7, characterized in that the active substance therein is a substance which can be rapidly tarnished, inactivated or excreted by the liver. &&&&& 83033 1 4