GB2026862A - Filaricide implants containing diethylcarbamazine - Google Patents

Abstract

Subcutaneous and intramuscular implants contain slowly available forms of diethylcarbamazine for controlling filaria parasites over an extended period of time.

Description

SPECIFICATION Filaricide implant This invention is concerned with compositions and methods for combatting filariasis in vertebrate animals, by subcutaneously or intramuscularly implanting slow release forms of dieththylcarbamazine.

Diethylcarbamazine is released from the implant into the bloodstream over a period of weeks or months by diffusion or bio-degradation or both of the wall material of the implant which is generally polymeric in nature.

Uncontrolled development of filaria parasites in a vertebrate animal causes symptoms of cardiopulmonary involvement including coughing, ascites and limb edema, and general debilitation as well as contributing to the spread of filariasis diseases via mosquitos and other invertebrate carriers to other vertebrate individuals.

Generally speaking, filariasis is a helminthic disease in which the parasite invades the body tissue and each species of vertebrate is afflicted by a different parasite. For example, Dirofilaria immitis is the most common cause of filariasis in canines whereas Wuchereria bancrofti and Wuchereria malayi are widely responsible for filariasis in humans.

Infection of the vertebrate animal begins with the deposit of infective third stage larvae on the skin by an invertebrate such as a mosquito. From there the larvae proceeds to go through two more molts and then adulthood. The adult female filaria produce micro-filaria in large numbers which circulate throughout the vertebrate body in the blood. The cycle continues when a mosquito takes blood from a host having microfilaria in the bloodstream and the microfilaria then matures within the mosquito to larvae stage. Thereafter the cycle is completed with another vertebrate being bitten by the carrier mosquito.

More specifically the present invention is concerned with providing means and methods for combatting the parasites which cause filariasis which steadily and continuously release diethylcarbamazine for its effect on killing filaria in the larva stage, its stunning effect in adult filaria of certain species, its effect on microfilaria directly and indirectly, its prophylactic effect to the host and its contribution to eradication of pockets of the disease among the animal and human population of the world.

The present invention provides novel compositions and methods of combatting and controlling filaria parasites in vertebrate animals. The novel compositions consist of encapsulated, i.e. slowly available forms of diethylcarbamazine for subcutaneous or intra-muscular implantation in vertebrate animals for the purpose of interfering with the reproductive cycle of filaria parasites which have infected the host vertebrate animal. These encapsulates provide a reservoir of diethylcarbamazine providing slow release of the compound into the bloodstream over an extended period of time of weeks or months, thus providing sustained effect against the parasite. Because the release is slow, anaphylactic problems in humans are alleviated and need for antihistamines and steroidal drugs is lessened and longer term control of the associated diseases is possible.

Generally speaking, the implants of this invention provide diethylcarbamazine blood levels of about 500 to 2500 nanograms/ml (5 to 25 nanograms %) of blood plasma for periods of 2-10 weeks in some cases and to 12 months in other cases.

It is therefore an object of the present invention to provide novel slowly-available forms of diethylcarbamazine for the purpose of implanting subcutaneously or intramuscularly in vertebrate animals to combat and control filaria parasites.

Another object is to provide a method of controlling filaria parasites in vertebrate animals particularly heart worms in dogs with diethylcarbamazine over an extended period of time without daily dosing.

Another object is to provide a method of eliminating or greatly reducing microfilaria counts in host vertebrates by killing filaria larvae with diethylcarbamazine administered as a slowly available implant, thus interrupting the life cycle.

Another object is to avoid stomach irritation usually associated with oral administration of diethylcarbamazine.

Another object is to provide a means of controlling filariasis in humans on a community-wide basis by a single treatment of individuals which remains effective for about 2-26 weeks.

Diethylcarbamazine which is N,N-diethyl-4methyl-piperazine carboxamide is the active filaricide agent used in the implants ofthis invention.

Generally the most useful chemical forms of the agent are the more soluble forms when simple diffusion of the agent from an implant is the mechanism by which distribution to the bloodstreams occurs. However, when biodegradable wall material is used for the implant, less soluble forms such as the citrate salt may also be employed.

The carrier or wall materials for carrying or encapsulating the diethylcarbamazine filaricide agent may be any material compatible with vertebrate animal flesh, i.e. non-reactive with animal tissue, in subcutaneous or intramuscular implantation, generally of plastics or polymeric nature outward from the implant. The implant may take the form of a matrix containing a dispersion of diethylcarbamazine agent or the form of a capsule having a central reservoir portion containing the agent or a solution or a suspension of the agent.Illustrative of suitable encapsulating or wall materials are those seiected from silastic, polyethylene, teflon, polylactides, polylactones, polycarbonates, polymers of p-dioxanone and 1,4-doxepan-2-one and alkyl derivatives thereof, ethyl, cellulose, nitrocellulose, cel luiose acetate phthalate, shellac, polyacrylic acid, polymethacrylic acid, polyvinylchloride, polyvinyl butyral, polyvinyl acetate, vinylic polymers, polys trvene poly-methacrylate, maleic anhydride copolymers, alkyd resin, and polybasic ester of cellulose.

Of the above recited encapsulating and wall materials, silastics, polycarbonates, polylactones, p-dioxanone polymers and polyhydric acid esters of cellulose and combinations thereof are preferred.

In general, there is a wide variation in amount of diethylcarbamazine filaricide agent contained in the encapsulates. For example, small pouches may contain up to 95% by weight of the agent and microencapsulates may contain from 5 to 95% by weight diethylcarbamazine.

A new gas-liquid chromatographic method for quantitative determination of diethylcarbamazine in blood plasma was developed. To samples containing diethylcarbamazine is added an internai standard, 1-diethylcarbamoyl-4-n-propylpiperazine and the sample is made basic with 0.1 N sodium hydroxide. The sample layer is extracted with chloroform and the chloroform layer containing the diethylcarbamazine is evaporated to dryness and then reconstructed in acetone. Diethylcarbamazine is then quantified by GLC equipped with a thermionic (nitrogen) detector. The chromatographic peaks due to diethylcambazine and the internal standard are separated on a column packed with 3% OV-225 on gas Chrom Q. The lower limit of detection for diethylcarbamazine by the foregoing method is 50 nanograms per ml of blood plasma.

As stated above, the implants of this invention will deliver 500-2500 nanograms/ml of blood plasma. By way of comparison to prior art oral administration using the foregoing method of anaylsis, blood plasma of a dog given an oral dose of 3.0 mg/kg of diethylcarbamazine reaches a peak level of 3000 nanograms per ml after administration and within about 4 hours the level falls to 50 nanograms/ml.

The invention may be put into practice in various ways and a number of specific embodiments will be described by way of example to illustrate to invention.

Example 1 Encapsulates of diethylcarbamazine are prepared as follows: Poly-L-lactide, 9 and diethylcarbama- zine powder, 1.0 g were mixed and warmed to the melting point of the lactide. The mixture was cooled and ground into a powder. Two grams of the powder were injected intramuscularly into a dog weighing 10 kg, suffering from heart-worm diseases which had been cleared of micro-filaria and adult heartworms, to kill infective filaria larvae thereby preventing larvae from reaching adult stage and also interfering in the stage of the reproductive cycle involving microfilaria.

Example 2 Encapsulates of diethylcarbamazine are prepared using as wall material poly(d,l-lactic) acid prepared from d,l-lactide monomer by melt polymerization using tetraphenyltin catalyst and lauryl alcohol to control molecularweightat 175"C.

A solution was prepared using 25 parts by weight diethylcarbamazine and 75 parts by weight of the poly (d,l-lactic) acid and sufficient chloroform to dissolve the mixture. A dispersion of this solution in a larger volume of 5% aqueous polyvinyl alcohol was prepared under agitation. The chloroform was removed under reduced pressure with continued agitation. The product contained about 25 weight percent diethicarbamazine. Dry microcapsules were then sized using an ATM Sonic Sifter (Registered Trade Mark).The microcapsules in the particle size range of 25-150 microns were administered in 1-49 dosages in saline solution via a 18 to 22 gauge needle intramuscularly to dogs in the condition described in Example 1 free of adults and microfilaria to kill filaria larvae in vertebrate animals and prevent development of microfilarae over a period of about 6 months.

Example 3 Poly-L-lactic acid was substituted for poly(d,llactic) acid in equal amount in the procedure of Example 2. The 25-150 micron-sized microcapsules obtained were administered as in Example 2 to vertebrate animals, to provide slow release of diethylcarbamazine over up to 12 months and control of filaria parasites by the prevention of reproduction of microfilaria during the slow release of the compound.

Example 4 Encapsulates of diethylcarbamazine were prepared as follows: 50 g of the polycarbonate of 2,2-bis (4-hydroxyphenyl)propane was dissolved in 50 cc of methylene chloride to prepare a solution. In this solution was dispersed 10 g of diethylcarbamazine.

This solution was emulsified to fine droplets in 150 ml of ethyleneglycol and the methylene chloride gradually evaporated. The solid microcapsules were collected by centrifuge and rinsed with water. The microcapsules were subcutaneously implanted in humans to obtain control over the production of microfilaria.

As stated hereinabove, the implants in the form of encapsulates release diethylcarbamazine such that the blood contains levels of about 5 to 25 nanograms %. As shown in the examples, various types of encapsulates may be used, all of which may have varying rates of release of the filaricide diethylcarbamazine and when taken with the variation in sizes of the vertebrate host, it can be readily realized that varying sizes of implants will be required depending on the situation. In general, however, the size of the implant will vary from about 0.5 to about 4 grams and if necessary multiple dosage forms may be administered to larger vertebrates. The amount of diethylcarbamazine in the implant may vary from about 5 to 95 wt%. Encapsulates may be inserted through a siit in the skin or in the case of microencapsules, administered by injection equipment beneath the skin or intramuscularly.

Claims (4)

1. A method of controlling filaria parasites in vertebrate animals which consists of administering subcutaneously or intramuscularly an implant comprising a slow release form of diethylcarbamazine, said implant supplying an amount of diethylcarba mazineto the bloodstream of the said animal sufficient to interfere with the life cycle of the said parasite in the larval stage and in the microfilariae reproduction phase.

2. A method as claimed in Claim 1 in which the vertebrate aminal is of the canine species and the filaria parasite is the heartworm.

3. The use of an implant as claimed in Claim 1 in which the vertebrate animal is a human and the filaria parasite is Wuchereria bancrofti or Wuchereria malayi.

3. A method as claimed in Claim 1 in which the vertebrate animal is a human and the filaria parasite is Wuchereria bancrofti or Wuchereria malayi.

4. Afilaricide implantforvertebrate animals comprising carrier material and diethylcarbamazine.

5. An implant as claimed in Claim 3 or 4 in which the carrier material is polylactide.

6. An implant as claimed in Claim 3 or 4 in which the carrier material is a polycarbonate.

7. An implant as claimed in Claim 4,5 or 6 in which the implant comprises microcapsules containing the active material.

8. An implant as claimed in Claim 4,5 or 6 in which the implant comprises solid particles, each particle being a blend of carrier material and active material.

9. A filaricide implant as claimed in Claim 4 substantially as specifically described herein with reference to any one of Examples 1 to

4.

New claims or amendments to claims filed on 7 Nov 1979 Superseded claims 1 to 3 New or amended claims:

1. An implant comprising a slow release form of diethylcarbamazine for use in a method of controlling filaria parasites in vertebrate animals, which method consists of administering subsutaneously or intramuscularly the said implant, the said implant being such as to supply an amount of diethylcarbamazine to the blood stream of the said animal sufficient to interfere with the life cycle of the said parasite in the larval stage and in the microfilariae reproduction phase.

2. An implant as claimed in Claim 1 in which the vertebrate animal treated is of the canine species and the filaria parasite is the heartworm.