ZA200907464B

ZA200907464B - Medicament formulation

Info

Publication number: ZA200907464B
Application number: ZA2009/07464A
Authority: ZA
Inventors: Alawi Fedil Al; Karthigeyan Nanjan; Wayne Frederick Leech
Original assignee: Bomac Research Ltd
Priority date: 2008-10-31
Filing date: 2009-10-23
Publication date: 2010-08-25
Also published as: GB0918912D0; IE20090833A1; GB2464825B; GB2464825A; NZ572491A

Description

: p , “2000/0744, [ MEDICAMENT FORMULATION \ WN) Pr Ca

TECHNICAL FIELD i :

The invention relates to an improved medicament formulation.

More specifically, the invention relates to a medicament for use and methods in the prevention or treatment of deficiencies in the elements iodine and selenium, particularly in relation to farm animals. oo

BACKGROUND ART

Element deficiencies in animals, including humans, are known to result in a variety of disease states. As a result many health supplements have been developed for . animals and humans to prevent element deficiencies and therefore avoid : associated disease states.

In the case of farm animals such as sheep and cattle, element deficiencies may occur as a result of nutrient deficiencies in feed which lacks one or more elements required for correct metabolic function. For example, brassica crops often used as an animal feed typically contain low levels of iodine.

In such cases, one solution used to prevent or treat the deficiency is to administer to the animal a dose of the element or elements either before onset of the disease state or as a treatment once symptoms of the disease are exhibited. In general, it is desirable that doses be long acting so that the dose need only be administered to an animal on an infrequent basis.

Two key elements which are commonly deficient when farming livestock such as sheep and cattle are the elements iodine and selenium. lodine is an essential element required by the thyroid gland for the manufacture of hormones thyroxine (T,), and tri-iodothyronine (T;). Deficiencies in iodine may lead oo 1a

® toa variety of diseases, the symptoms and effects of which are often accentuated in young growing animals. By way of example, iodine deficiency diseases such as goitre and may be associated with prolonged gestation, dystocia and reduced survival of progeny. Also, iodine deficiency of the foetus in a ewe may influence progeny tissue growth and tissue differentiation, resulting in development abnormalities in the central nervous system, gonads, heart, skin, wool and follicles of progeny. | | E ; One widely used and long acting iodine medicament is Flexidine™ manufactured by Bomac Laboratories Ltd. This is a clear to slightly cloudy oily liquid medicament for administration preferably by injection into the muscle (intramuscularly). The primary constituent of the medicament is iodised peanut oil. The iodine (approximately 26% w/v of the medicament) is bound to ethyl esters of the : unsaturated fatty acids in peanut oil (primarily oleic and linoleic). This medicament provides an animal approximately 12 months or more of sustained levels of iodine or at least sufficient amounts to avoid disease states associated with iodine deficiencies. One advantage of this product is that it has few adverse site reactions and does not cause pain.

The iodised oil has a delayed mode of action in that, over time, the oil is slowly released from the depot and is taken up by the lymphatic system, making its way to the regional lymph nodes. At the lymph nodes, the oil is metabolised into constituent fatty acids and free iodine over a lengthy duration.

Selenium is an essential component of many enzymes which have broad ranging functions. Deficiency of selenium is associated with many conditions and diseases oo such as white muscle disease, cystic ovaries, early and late embryo death, mastitis . 25 and increased somatic cell counts, and Keshan disease (or cardiac muscle degeneration). )

[| A long acting selenium medicament is Deposel™ also manufactured by Bomac

Laboratories Ltd. Deposel™ is a yellow coloured free flowing aqueous suspension * formulated for administration by injection subcutaneously. The primary constituent of the medicament is barium selenate and the medicament provides approximately 50mg of selenium per ml of medicament.

Like Flexidine™, Deposel™ provides a source of selenium to a treated animal for over approximately 12 months. One disadvantage of Deposel™ is that the medicament may be associated with adverse site reactions such as irritation and scarring. A further problem with the Deposel™ medicament is that creepage of the : 10 depot can occur with the depot eroding away quicker than is desirable. :

Although both of the above iodine and selenium medicaments are widely used, one oo disadvantage is that these are separate treatments and therefore, in animals deficient in both elements, separate administration of each medicament is required which is costly in terms of time and labour.

In attempt to overcome this disadvantage, the current applicants previously developed a combination medicament (Flexidine Plus™ which administered both of - the barium selenate and iodised peanut oil used in Deposel™ and Flexidine™ ‘respectively, as described in granted New Zealand Patent No. 538587.

This combination medicament was a difficult task to achieve as the active elements, namely barium selenate and iodine, typically do not mix well, which can lead to problems during storage and administration. After considerable effort the applicant devised a formulation which provided improved stability and bioavailability characteristics when compared to when Flexidine™ and Deposel™ were simply : mixed together for a dual administration.

However, although the applicant was able to drastically improve the ease of administration of these active ingredients together as one combination

@® medicament the barium selenate sometimes clumped together, sedimented or caked on long standing. Furthermore, the formulation was particularly susceptible to these problems when the formulation was stored at lower temperatures (for example, 0 — 15°C).

Therefore, whilst the applicant’s ability to provide a combination formula was successful, there remained a considerable need to devise an improved formulation

B which avoids these issues which still persisted occasionally.

It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice.

All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country.

It is acknowledged that the term ‘comprise’ may, under varying jurisdictions, be attributed with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term ‘comprise’ shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. This rationale will also be used when the term ‘comprised’ or ‘comprising’ is used in relation to one or more steps in a method or process.

Further aspects and advantages of the present invention will become apparent . from the ensuing description which is given by way of example only.

@ DISCLOSURE OF INVENTION 04

According to one aspect of the present invention there is provided a medicament : formulated for parenteral administration, wherein the medicament includes: (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and, (c) at least one lipophilic oily solvent. : According to a further aspect of the present invention, there is provided a method of prevention or treatment of an element deficiency in iodine or selenium or both, in an animal by parenteral administration of a medicament including: (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and, _ (c) atleast one lipophilic oily solvent. "According to a further aspect of the present invention, there is provided a method . of prevention or treatment of a disease in an animal associated with a deficiency in oa 15 elements selected from iodine, selenium or both, by parenteral administration of a _ . medicament including: (a) iodised unsaturated vegetable oil; : (b) micronised barium selenate; and, (c) atleast one lipophilic oily solvent.

According to a further aspect of the present invention there is provided use of: : (a) iodised unsaturated vegetable oil; ;

® (b) micronised barium selenate; and, oo 4 ~ (c) atleast one lipophilic oily solvent in the manufacture of a medicament for parenteral administration formulated for the prevention or treatment of a deficiency in elements including iodine, selenium or both.

According to a further aspect of the present invention there is provided use of: (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and, : (c) at least one lipophilic oily solvent © 10 in the manufacture of a medicament formulated for parenteral administration in the _ prevention or treatment of a disease in an animal associated with a deficiency in elements including iodine, selenium or both.

Previously, the applicants disclosed a combination formulation which included both iodised unsaturated vegetable oil and micronised barium selenate. This break- : 156 through held a significant advantage as both actives could be administered : together, avoiding unnecessary time and labour in administering each active separately as two medicaments.

The difficulty in providing two medicaments together lay in the ability to maintain the two medicaments in a single solution which has considerable stability. This ~ 20 invention was to provide a combination medicament which was substantially : improved compared to simply mixing the Flexidine™ and the active of Deposel™ together. However, the formulation medicament was still susceptible at times to clumping and caking of the barium selenate with storage. :

® Previously, significant experimentation was not sufficient to identify a component that completely prevented this unwanted effect. Many solvents were trialled in the formulation and some of these were shown to dramatically improve the dispersion “and uniformity characteristics of the composition. The best solvent tested was found to be ethyl oleate. It was thought that this solvent may reduce the viscosity of the iodised peanut oil, hence allowing uniform dispersion of the barium selenate.

Regardless, after considerable experimentation into potentially useful solvents, ethyl oleate still led to unwanted clumping/ and caking with time. Therefore, there remained a considerable need to improve the formulation without these unwanted characteristics.

The formulation provided in the current application overcomes these unwanted effects. oo The use of a lipophilic oily solvent, preferably mineral oil as a solvent has a dramatic effect on the formulations stability and dispersion, and prevents the clumping/ and caking encountered with the previously discussed formulation. The use of this particular type of solvent has no harmful effect on animals and does not appear to decrease the bioavailability of the active ingredients.

Mineral oil is often consumed by humans where it acts as a laxative, highlighting its safety for use in formulations and in the human body. It is also used in baby oils for skin ointment. Various typés of veterinary medicine also utilise mineral oil as an -adjuvant to stimulate cell-mediated immune responses to the vaccinating agent.

Furthermore, mineral oil is also used as a parasitic agent, where it is applied to the feet of chickens where it suffocates the mites which live there. As can be seen, mineral oil is used in a variety of different medical applications, highlighting its : 25 safety.

An additional advantage of mineral oil is that it is inexpensive and can be obtained : .

Claims

WHAT WE CLAIM IS: Pi : a :

1. A medicament formulated for parenteral administration, wherein the . medicament includes: (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and (c) paraffin oil.

2. The medicament as claimed in claim 1 wherein the iodised unsaturated vegetable oil is selected from: peanut oil; poppy seed oil; rape seed oil; olive oil; soya oil; walnut oil; and combinations thereof. :

3. The medicament as claimed in claim 1 or claim 2 wherein the iodised unsaturated vegetable oil is peanut oil including 20 - 30% w/v iodine bound to ethyl esters of the unsaturated fatty acids in the peanut oil.

4. The medicament as claimed in any one of claims 1 to 3 wherein the iodised oil constitutes 85 - 95% wiv of the medicament.

5. The medicament as claimed in any one of claims 1 to 4 wherein micronised barium selenate is in the form of a micronised powder suspended within the oo iodised oil immediately prior to administration.

6. The medicament as claimed in any one of claims 1 to 5 wherein the micronised barium selenate constitutes 5 - 10% w/v of the medicament.

7. The medicament as claimed in any one of claims 1-to 6 which has the % w/v - of paraffin oil required to bring the formulation to a predetermined volume.

8. The medicament as claimed in any one of claims 1 to 7 wherein the paraffin oil constitutes 10 - 20% w/v of the medicament.

@ 9. A medicament as claimed in any one of claims 1 to 8 wherein the medicament includes a preservative.

10. The medicament as claimed in any one of claims 1 to 9 wherein the preservative is benzyl alcohol.

11. The medicament as claimed in any one of claims 1 to 10 wherein the medicament includes a wetting agent. .

12. The medicament as claimed in any one of claims 1 to 11 wherein the wetting agent is sorbitan monooleate. -

13. Use of:

{ . : (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and (c) paraffin oil in the manufacture of a medicament for parenteral administration formulated Co for the prevention or treatment of a deficiency in elements including iodine, : © selenium, or both.

14. Use of: (a) iodised unsaturated vegetable oil; : (b) micronised barium selenate; and (¢) paraffin oil in the manufacture of a medicament formulated for parenteral administration in the prevention or treatment of a disease in an animal associated with a - deficiency in elements including iodine, selenium or both.

- | te: : “2009/0744, Q 15. A method of manufacture of a medicament containing iodine and selenium formulated for parenteral administration including the steps of: (a) mixing benzyl alcohol with sorbitan mono-oleate; and (b) mixing the mixture of step a) with iodised unsaturated vegetable oil; and oo “(cy mixing the mixture of step b) with micronised barium selenate ‘powder; and, hE (d) mixing the mixture of step c¢) with paraffin oil.

16. The method according to claim 15 wherein nitrogen gas is bubbled through the mixture of step (d). Co | oo :

17. A medicament substantially as herein described with reference to Table 1 of the specification.

18. The medicament as claimed in claims 1 or 17, substantially as herein described with reference to and/or as illustrated by any of the tables. :

19. The use as claimed in claims 13 or 14, substantially as herein described with reference to and/or as illustrated by any of the tables.

20. The method according to claim 15, substantially as herein described with : reference to and/or as illustrated by any of the tables. Dated this. 23" day of October 2009 oo Adams & Adams : Applicants Patent Attorneys oo EA