JP2001517622A - Parasiticide - Google Patents

Abstract

  (57) [Summary] The present invention provides a solid implant comprising at least one parasiticidal compound having low water solubility; and excipients for tableting, including bulking agents. Implants according to the invention are convenient for the recipient and provide long-term protection against parasites.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a solid implant containing a parasiticidal compound having low water solubility,
It is particularly useful for administration to livestock such as cattle, pigs and sheep.

[0002] A number of potent macrocyclic parasiticidal compounds are known, including avermectins and milbemycins. GB N ⁰ No. 1,573,955 is in a group of avermectin compound represented by killing parasitic raw product drugs (including avermectin B1a and B1b) disclosed.

[0003] 22,23-Dihydroavermectin B1 (disclosed in ivermectin, EP 1689) is commercially available in an injectable formulation (sold as IVOMEC ^™ ). Ivermectin contains at least 80% of 22,23-dihydroavermectin B1a (having 25-sec-butyl groups) and 20%
It is a mixture of the following 22,23-dihydroavermectin B1b (having a 25-isopropyl group).

[0004] 25-cyclohexyl avermectin B1 (Dramectin, EP214731)
Has the following structure:

[0005]

Embedded image

And is commercially available in an injectable oil formulation (sold as DECTOMAX ^™ ) for the treatment and prevention of bovine in vivo and extracorporeal parasite infestations. The oily preparations are described in EP ⁰ 393 890.

[0007] Milbemycins are similar in structure to avermectins, except that they are not substituted at position 13.

[0008] Formulations such as DECTOMAX ^™ have been successful, but are convenient for the user,
Moreover, there is a further need for formulations that provide long term protection against parasites.

[0009] European Patent Application No. 240274 discloses the use of avermectins as growth promoters. European Patent Application No. 313195 discloses the use of avermectins in the prevention of bollworm poisoning when grazing animals. Neither specification claims subcutaneous implants, but teaches how to make such implants.

[0010] EP 473 223 discloses complex biodegradable implants in which an active substance such as an anthelmintic is covalently contained in the backbone of the component polymer.

[0011] EP 579998 discloses a drug delivery device composed of a polymeric matrix, a vehicle (which is a plasticizing solvent for the polymeric matrix) and a drug. The drug may be avermectin or milbemycin, and the device is intended for local delivery of the drug, such as a pet flea or mites collar.

Thus, the present invention provides a solid implant comprising at least one parasiticidal compound having low water solubility; and a tableting excipient including a bulking agent.

An important feature of the implants of the present invention is their simplicity. Thus, preferably, more than 95%, more preferably more than 99%, by weight of the implant will be composed of the parasiticidal compound and the excipient for tableting.

An implant according to the invention may be implanted intramuscularly. However, preferably, they are implanted subcutaneously (ie, in adipose tissue just below the skin).

[0015] Suitable parasiticidal compounds are those having an aqueous solubility of less than 100 μg / ml, such as avermectin or milbemycin. Doramectin is of particular interest (has an aqueous solubility of 0.6 μg / ml at pH 7). Ivermectin is also interesting.

[0016] Preferably, the bulking agent is lactose. Other suitable bulking agents include other sugars,
Includes microcrystalline cellulose (commercially available as AVICEL ^™ ) and dicalcium phosphate.

[0017] Other tableting excipients that may be present include magnesium stearate, which acts as a lubricant to facilitate tableting. Typically, magnesium stearate will make up about 3% by weight of the implant. The formulation may also include a binder to aid granulation and tableting. Examples of binders include starch, gelatin and polyvinylpyrrolidone. Typically, the binder, when present, will comprise from 2 to 10% by weight of the implant.

Yet another tableting excipient that the implantable tablet of the present invention may contain is a tablet disintegrant. Suitable disintegrants include sodium starch glycolate, which is commercially available as EXPLOTAB ^™ . Other disintegrants that may be mentioned are dicalcium phosphate and cross-linked starch. Typically, disintegrants, when present, will comprise about 5% by weight of the implant.

[0019] Preferably, the (or multiple) parasiticidal compound is present in the implantable tablet in 10-60.
By weight, more preferably 20-45% by weight of the implant, for example 40% by weight.

Preferably, the implant of the present invention contains an antioxidant or a reducing agent. Such additives have been found to reduce or eliminate the degradation of the parasiticidal compound, thereby extending the shelf life of the implant. Such additives have been found to be particularly useful for stabilizing the parasiticidal compound when the implant is sterilized by irradiation, such as gamma or beta irradiation.

A particularly interesting antioxidant is butylated hydroxyanisole (BHA; 2-t)
a mixture of tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol) and butylated hydroxytoluene (BHT; 2,
6-di-tert-butyl-4-methylphenol). Other antioxidants and reducing agents include α-tocopherol, alkyl gallate derivatives, nordihydroguaiaretic acid, ascorbic acid, sodium metabisulfite and sodium sulfite. Typically, antioxidants, when present, are present in the implant at 0.01%.
~ 0.5% by weight, more preferably 0.1-0.2% by weight.

As mentioned above, the implants of the present invention can be sterilized by irradiation, typically at a dose in the range of 15 to 25 kGy (kilo grey).

The implants of the present invention may be implanted at various sites in the animal to be treated, for example, on the flank, base of the tail or ears. If the ears are removed during the meat feeding process, this is the preferred site for implantation.

To facilitate such implantation, the implants are preferably rod-shaped and can be conveniently implanted using a conventional manual implant gun. Suitably, the rod-shaped implant is 2-30 mm long and 2-5 mm diameter. Preferred dimensions are 5
6 mm long and 2-3 mm diameter. Preferably, its cross section is circular.

According to the present invention there is further provided a method of treating or preventing a parasitic infection, said method comprising administering to an animal in need of such treatment an implant as defined above. .

[0026] Parasite infections of particular interest are those caused by endoparasites, including helminths, most often caused by nematodes in the gastrointestinal tract. The implants are also useful in treating or preventing ectoparasite infections such as ticks, small mites, lice, fleas, blowflies, biting insects and migratory dipteran larvae.

The dosage administered will be dependent on the animal being treated, the parasiticidal compound being used and the condition being treated. However, a suitable dose of Doramectin is 0.5 mg / kg of animal body weight. Typically, an implant according to the invention having the preferred dimensions described above will contain about 10 mg of doramectin. Thus, a cow weighing 120 kg would require six implants. It is believed that this could provide sustained release of Doramectin for up to 120 days. If multiple implants are required, they can often be implanted sequentially with a single actuation of the implant gun.

The implants according to the invention can be released slowly in the case of cattle throughout the grazing period, so that the administration required is only once a year. Accordingly, the present invention provides the use of avermectin or milbemycin in the manufacture of an implant for the treatment or prevention of a parasitic infection, characterized in that the agent is administered once a year.

[0029] The implantable tablet of the present invention can be manufactured by dry or wet mass granulation, pulverized using a conventional technique, and tableted into a desired shape.

For example, an implant comprising doramectin, lactose and magnesium stearate may be manufactured by dry mass granulation using the following steps.

1. 1. Blend components except magnesium stearate 2. Sieving by screen 3. Blend 4. Add half of the magnesium stearate 5. Blend 6. Compress to slug 7. Pulverize the slug into granules. 8. Collect desired granule size fraction Blend 10. 10. Add remaining magnesium stearate Blend 12. The process of tableting into a wet bar is similar except that some components are dissolved in a solvent that is later removed and sprayed onto the other components while simultaneously blending them. In addition, binders are used to help adhere individual particles. For example, BHA and the binder PVP
In the case of the manufacture of an implant containing, BHA and PVP can be added to the blended mixture of components by spraying as a solution in ethanol. Therefore, doramectin, lactose, sodium starch glycolate, BHA, P
Implants consisting of VP and magnesium stearate may be manufactured by wet lump granulation using the following steps.

[0032] 1. 1. Blend components except magnesium stearate, BHA and PVP 2. Sieving by screen 3. Blend 4. Spray a solution of BHA and PVP in ethanol onto the mixture while mixing. 5. Wet the wet material 6. Dry to granules 7. Finely pulverize 8. Collect desired size fraction Blend 10. 10. Add magnesium stearate Blend 12. Tableting into a rod Thus, according to another aspect of the present invention, there is provided a method of making an implant as defined above, comprising mixing a parasiticidal compound with a tableting excipient and forming the desired shape. The above method is provided, comprising:

The duration of action of the implants of the present invention can be determined by measuring bovine plasma levels after implantation. These levels are about 2 ng / ml for effective control of helminths.
Correlated with the antiparasitic activity of a compound determined to need to maintain a plasma level of about 5 ng / ml for effective suppression of single host ticks I have.

In a broader aspect, the invention further provides the use of an antioxidant or a reducing agent to prevent the degradation of avermectin or milbemycin in a composition containing avermectin or milbemycin. BHA has traditionally been used in DECTOMAX ^™ with Doramectin, but its function was to prevent rancidity of the oily formulation, rather than to help the stability of Doramectin in solution. This embodiment, which aids the stability of the doramectin of the present invention, is particularly useful when irradiating the formulation and can be used in liquid and non-liquid formulations (such as solids and powders).

The present invention will be described in detail by the following examples and the accompanying drawings. Example 1 Doramectin Implantable Tablet

[0036]

[Table 1]

The ingredients except magnesium stearate were blended together in a blender for 15 minutes. Next, the blend was sieved through a 680 μm mesh screen and blended for an additional 15 minutes. Thereafter, half of the magnesium stearate was added and the blend continued for 5 minutes, after which the blend was compressed to form a "slug". Next, the slugs were pulverized to form granules, and a size fraction of 250 to 355 μm was collected.

Next, the collected granules were blended for 15 minutes, then the other half of the magnesium stearate was added and the blending continued for 5 minutes. The blend was then tableted with a suitable tablet press using a 2 mm mold to produce rod implants 2 mm in diameter and 5 mm in length.

Example 2 Doramectin Implants Containing Tablet Disintegrant

[0040]

[Table 2]

An implant was produced by the method of Example 1. Example 3 Pharmacokinetic Aspects The implants of Examples 1 and 2 were implanted in 16 cows at a dose of 500 μg / kg. The plasma concentration of Doramectin after implantation was measured and the results are shown in FIG. In each case, it can be seen that single host tick activity was obtained for over 50 days and helminth control was obtained for about 90 days.

Example 4 Doramectin Implants Containing Antioxidants

[0043]

[Table 3]

The ingredients except magnesium stearate, butylated hydroxyanisole and polyvinylpyrrolidone were blended together in a blender for 15 minutes. next,
The blend was sieved through a 680 μm mesh screen and blended for an additional 15 minutes. Thereafter, butylated hydroxyanisole and polyvinylpyrrolidone were dissolved in ethanol to form a granulation liquid. The volume of ethanol used was about 20% by weight of the total formulation. The granulation liquid was sprayed onto the blend for 10 minutes with constant mixing. The obtained wet granular material was sieved through a 1.4 mm mesh screen and dried under vacuum at 50 ° C. for 3 hours. Next, the dried granules were pulverized to collect a size fraction of 250 to 355 μm.

Next, the collected granules were blended for 15 minutes, magnesium stearate was added, and the blending continued for another 5 minutes. The blend was then tableted with a suitable tablet press using a 2 mm mold to produce rod implants 2 mm in diameter and 5 mm in length.

The implants were used in stability experiments to study the effects of BHA and electron beam irradiation. Doramectin remaining after 30 weeks storage at 30 ° C. of implants containing 0.5% w / w BHA and treated with four different irradiation levels [control (0 kGy), 15 kGy, 20 kGy and 25 kGy] Was measured. B
A control implant without HA was also tested.

FIG. 2 shows the results. It can be seen that the presence of BHA dramatically improves the storage stability of the implants, even when irradiated.

[Brief description of the drawings]

FIG. 1 shows the bovine plasma levels achieved with the implants produced in Examples 1 and 2.

FIG. 2 shows the disassembly profile of the implant manufactured in Example 4.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission Date] March 22, 2000 (2000.3.22)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // C07H 17/08 C07H 17/08 L (81) Designated country 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, KE, 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, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, G , GE, GH, GM, HR, HU, ID, IL, 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 , ZWF term (reference) 4C057 BB03 DD01 KK19 4C076 AA38 BB32 BB36 CC34 DD37S DD39S DD41 DD67 EE16 EE38B FF04 FF06 FF31 FF51 FF63 4C084 AA17 AA27 BA44 MA05 MA35 MA67 NA03 NA10 NA12 ZB01 MA03 MA02 NA12 ZB37 ZC61

Claims (21)

[Claims] A solid implant comprising at least one parasiticidal compound having low water solubility; and excipients for tableting, including bulking agents. 2. The implant according to claim 1, adapted for subcutaneous implantation. 3. The implant according to claim 1, wherein the parasiticidal compound has an aqueous solubility of less than 100 μg / ml. 4. The implant according to claim 3, wherein the parasiticidal compound is avermectin or milbemycin. 5. The implant according to claim 4, wherein the parasiticidal compound is doramectin. 6. The implant according to claim 1, wherein the bulking agent is lactose. 7. The implant according to claim 1, wherein the tableting excipient comprises magnesium stearate. 8. The implant according to claim 1, wherein the tableting excipient comprises a tablet disintegrant. 9. The implant according to claim 8, wherein the tablet disintegrant is sodium starch glycolate. 10. The implant according to claim 1, which contains an antioxidant or a reducing agent. 11. The implant according to claim 10, wherein the antioxidant is butylated hydroxytoluene or butylated hydroxyanisole. 12. The implant according to claim 1, which is suitable for or sterilized by irradiation. 13. The tablet-forming excipient comprises polyvinylpyrrolidone.
13. The implant according to any one of claims 12 to 12. 14. The implant according to claim 1, wherein the parasiticidal compound comprises 10% to 60% by weight of the implant. 15. The method according to claim 1, which is adapted for implantation into the ear of a cow or sheep.
5. The implant according to any one of the above items 4. 16. The implant according to claim 1, which is in the form of a rod. 17. Use of an antioxidant or a reducing agent for preventing the degradation of avermectin or milbemycin in a preparation containing avermectin or milbemycin. 18. Use according to claim 17, wherein the formulation is suitable or sterilized for irradiation sterilization. 19. Use according to claim 17 or claim 18, wherein the formulation is not a liquid. 20. The method of making an implant according to claim 1, comprising mixing the parasiticidal compound with a tableting excipient and shaping into a desired shape. 21. A method for treating or preventing a parasitic infection, comprising administering to an animal in need of such treatment an implant according to any one of claims 1 to 16. The above method.