AU2009230806B2 - Improved medicament formulation - Google Patents

Abstract

The invention relates to a parenteral medicament that includes iodised unsaturated vegetable oil, micronised barium selenate, and at least one lipophilic oily solvent. Uses and methods associated with this medicament are described whereby the 5 medicament is administered to an animal and subsequently provides a slow release amount of iodine and selenium to the animal from the one formulation, therefore preventing deficiencies and diseases associated with these elements. By utilising a lipophilic oily solvent in the formulation, the inventors have found that it is possible to completely overcome dispersion problems associated with combining 10 iodised unsaturated vegetable oil and barium selenate.

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant(s): Bomac Research Limited Invention Title: Improved medicament formulation The following statement is a full description of this invention, including the best method for performing it known to me/us: 2 IMPROVED MEDICAMENT FORMULATION TECHNICAL FIELD The invention relates to an improved medicament formulation. More specifically, the invention relates to a medicament for use and methods in the 5 prevention or treatment of deficiencies in the elements iodine and selenium, particularly in relation to farm animals. 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 10 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 15 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 20 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.

3 Iodine is an essential element required by the thyroid gland for the manufacture of hormones thyroxine (T 4 ), and tri-iodothyronine (T 3 ). Deficiencies in iodine may lead to a 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 5 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. 10 One widely used and long acting iodine medicament is FlexidineTM 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 15 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. 20 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 25 functions. Deficiency of selenium is associated with many conditions and diseases such as white muscle disease, cystic ovaries, early and late embryo death, mastitis 4 and increased somatic cell counts, and Keshan disease (or cardiac muscle degeneration). A long acting selenium medicament is DeposelTM also manufactured by Bomac Laboratories Ltd. DeposeTM is a yellow coloured free flowing aqueous suspension 5 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 TM, DeposeTM provides a source of selenium to a treated animal for over approximately 12 months. One disadvantage of DeposelTP is that the 10 medicament may be associated with adverse site reactions such as irritation and scarring. A further problem with the DeposelTM medicament is that creepage of the 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 disadvantage is that these are separate treatments and therefore, in animals 15 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 PlusTM which administered both of the barium selenate and iodised peanut oil used in Deposel 'and FlexidineTM 20 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 25 characteristics when compared to when Flexidine and DeposeTM were simply 5 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 5 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 0 C). Therefore, whilst the applicant's ability to provide a combination formula was successful, there remained a considerable need to devise an improved formulation 10 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 15 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 20 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 25 listed components it directly references, but also other non-specified components 6 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. 5 DISCLOSURE OF INVENTION 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, 10 (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; 15 (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 a disease in an animal associated with a deficiency in elements selected from iodine, selenium or both, by parenteral administration of a 20 medicament including: (a) iodised unsaturated vegetable oil; 7 (b) micronised barium selenate; and, (c) at least one lipophilic oily solvent. According to a further aspect of the present invention there is provided use of: (a) iodised unsaturated vegetable oil; 5 (b) micronised barium selenate; and, (c) at least 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. 10 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 in the manufacture of a medicament formulated for parenteral administration in the 15 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 through held a significant advantage as both actives could be administered 20 together, avoiding unnecessary time and labour in administering each active separately as two medicaments.

8 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 invention was to provide a combination medicament which was substantially improved compared to simply mixing the Flexidine and the active of DeposelTM 5 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 10 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 15 remained a considerable need to improve the formulation without these unwanted characteristics. The formulation provided in the current application overcomes these unwanted effects. The use of a lipophilic oily solvent, preferably mineral oil as a solvent has a 20 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 25 safety for use in formulations and in the human body. It is also used in baby oils for skin ointment. Various types of veterinary medicine also utilise mineral oil as an 9 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 5 safety. An additional advantage of mineral oil is that it is inexpensive and can be obtained in large quantities. A significant advantage of the use of a lipophilic oily solvent prevents "cloudiness" (and stability of the mixture) at lower temperatures which are used during storage 10 usually between 0 - 15'C. Furthermore, the use of this type of solvent also prevents clumping/ and caking of the suspended active with time Both problems were observed in the former formulation. Unexpectedly, the use of a lipophilic oily solvent totally avoids this undesired effect. It is important to note that veterinarians are trained to usually discard and/or not 15 use any medicament in solution that has a cloudy appearance. This is because such appearances usually suggest that the therapeutic composition is out of date or is ineffective/unsafe for use. However, the commercially available combination FlexidineTm and Depose TM formulation (Flexidine Plus T M ) is often slightly cloudy, yet is still effective and safe for use. Therefore, providing a combination 20 Flexidine TM and DeposelT formulation that does not have this cloudy or clumpy/cakey appearance may be highly advantageous as it may avoid unnecessary disposal of the formulation by veterinarians or other users. The lipophilic oily solvent also aids the two components to remain as one entity upon parenteral injection. This also helps provide the long acting release effect 25 intended for this combination medicament.

10 The lipophilic oil may be any type of mineral oil which provides the desired results. However, the applicant acknowledges that the lipophilic oily solvent could be other solvents and not limited to mineral oils. There are three basic classes of mineral oils, these include paraffin oils based on 5 N-alkanes, naphthenic oils based on cycloalkanes, aromatic oils, based on aromatic hydro carbons. Preferably the mineral oil to be used as a solvent is paraffin oil. The applicants wish to emphasise that the inventive concept lies in the discovery that to prevent clumping and caking of the barium selenate. This is expected to be the result of 10 the flocculation effect induced by the aliphatic and cyclic hydrocarbons of the lipophilic oily solvent, aided by the wetting agent in the formulation, on the suspended micronised barium selenate. This makes the barium selenate to be loosely packed and not bond tightly to each other, hence presenting the clumping and caking. Any sediment that does occur is easy to redisperse, so as to form the 15 original suspension. Preferably, the lipophilic oily solvent is approximately between 5-30% w/v of the final composition. Most preferably, the lipophilic oily solvent is approximately 16% w/v of the final composition. The applicants have found this amount to be most effective to prevent clumping and caking of the barium selenate. 20 The applicants unexpectantly discovered that this non polar solvent (lipophilic oily solvent) is required to disperse and stabilise the barium selenate within the iodised vegetable oil. Therefore the applicant emphasises that the current invention should not be limited to mineral oil as such, and recognises that other solvents with similar physical properties, like vegetable oils, glycerides (mono, di or tri) and their 25 esters, may be suitable for the current application.

11 Preferably, 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. Most preferably, the iodised oil is peanut oil. Preferably, the iodised oil used in the above medicament may include 5 approximately 26% w/v iodine bound to ethyl esters of the unsaturated fatty acids (primarily oleic and linoleic) in the oil. This is comparable to the existing FlexidineTM product which is known to be successful and provide long acting and adequate amounts of iodine to animal to avoid iodine deficiencies. In preferred embodiments it is envisaged that the iodised oil may constitute 10 approximately 90% w/v of the medicament. Preferably, barium selenate may be in the form of a micronised powder dispersed within the iodised oil. More preferably, the barium selenate may be a micronised powder with a particle distribution whereby 50% of the particles are less than 5 microns, 95% of the particles are less than 11 microns and 100% of the particles 15 are less than 22 microns in size. It is envisaged by the inventors that micronised barium selenate may constitute approximately 8.75% w/v of the medicament. Preferably, the medicament may also include one or more excipients such as preservatives and wetting agents. In a preferred embodiment, the inventors have found that the preservative may be benzyl alcohol and the wetting agent may be 20 sorbitan mono-oleate in order to produce optimum re-suspension characteristics and to prevent caking or clumping of micronised barium selenate particles. However, other preservatives and wetting agents with similar re-suspension and anti-caking properties are also envisaged as being used. In one preferred embodiment, the medicament includes iodised peanut oil, mineral 25 oil, micronised barium selenate, benzyl alcohol and sorbitan mono-oleate.

12 Preferably, the medicament is administered to an animal, for example a sheep or cow. This should not be seen as limiting as the invention may also be used in many other animals. Preferably, the formulation is shaken before administration to fully suspend and 5 distribute micronised barium selenate particles in the formulation. Preferably, the medicament is administered subcutaneously but may be administered intramuscularly. In one embodiment, the medicament may be administered into the anterior half of the neck of the animal. Preferably, where the medicament is used in treatment of an element deficiency or 10 associated disease, the medicament may be administered when the deficiency is diagnosed. Preferably, where the medicament is used to prevent a deficiency, the medicament may be administered: > To a ewe before mating or at least two months prior to lambing; 15 > To lambs as necessary, most preferably at weaning; > To rams approximately one month before mating; > To feed stock at least two months before feeding goitre drops. It is envisaged by the inventors that the medicament from the preferred embodiment may provide approximately 25 mg of selenium per ml of medicament 20 administered. It is further envisaged that the medicament from the preferred embodiment may provide approximately 195 mg of iodine per ml of medicament administered.

13 According to a further aspect of the present invention there is provided 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 5 b) mixing the mixture of step a) with iodised unsaturated vegetable oil; and c) mixing the mixture of step b) with micronised barium selenate powder; and, d) mixing the mixture of step c) with at least one lipophilic oily solvent. Preferably, nitrogen gas is bubbled through the mixture of step d). 10 Preferably, the steps in the method are undertaken in aseptic conditions. It should be appreciated from the above description that there is provided a medicament capable of providing a long acting source of both iodine and selenium. As the selenium source is dispersed in a lipophilic oily solvent, the medicament has the advantage of being able to be administered intramuscular or subcutaneous and 15 avoid problems associated with parenteral administration such as site reactions, irritation and egress of medicament. The medicament may be used as a prevention method to avoid a deficiency or, as a treatment method once a deficiency is diagnosed. Importantly, the current formulation utilises a mineral oil as a solvent which 20 overcomes the clumping/ caking effects often encountered from the applicant's previous formulation which utilises ethyl oleate as a preferred solvent. Considering the substantial time and effort devoted to providing a composition preferably without these effects, it would be clearly evident to those skilled in the art that arriving art the current invention (specifically the utilisation of a lipophilic oily 14 solvent) would not be obvious, otherwise this type of solvent would surely have been tested and applied previously through the applicant's investigations. BRIEF DESCRIPTION OF DRAWINGS Further aspects of the present invention will become apparent from the ensuing 5 description which is given by way of example only and with reference to the accompanying drawings in which: Table 1 A table showing a preferred formulation which includes a lipophilic oily solvent; and Table 2 A table showing the good stability of a preferred formulation which 10 includes a lipophilic oily solvent. BEST MODES FOR CARRYING OUT THE INVENTION TABLE 1 Below is the applicant's preferred formulation which utilises mineral oil (paraffin oil) as the lipophilic oily solvent. 15 TABLE 1 SI no Ingredients %wlv Use 1 Barium selenate micronised 8.875 Active 2 Benzyl alcohol 1.00 Preservative 3 sorbitan mono oleate (span 80) 0.3 wetting agent 4 lodised peanut oil 90 Active 5 Liquid paraffin, heavy gs Vehicle It should be noted that during the manufacturing process that all manufacturing steps are carried out aseptically and all raw materials are pre-sterilised. The method by which this formulation is prepared is as follows.

15 1. Mix the required amount of benzyl alcohol with sorbitan monooleate and mix (approximately 15 minutes). Then add to the required iodised peanut oil. 2. Mix till it is clear (approximately 20 minutes). 3. Add and suspend the micronized barium selenate powder to the bulk. Stir to 5 assure good suspension (approximately 50 minutes). 4. Add the paraffin oil and make to the volume. Mix well (approximately 15 minutes). 5. Homogenise the bulk using high shear homogeniser to get a smooth homogeneous suspension (approximately 15 minutes). 10 6. Pack and purge nitrogen gas in the appropriate container. TABLE 2 Table 2 provides the results from a six month stability analysis of a formulation which includes a lipophilic oily solvent. Importantly, it is evident that the iodine and selenium in this formulation remain in solution and are stable at 40'C/75% RH for 15 six months. This is a significant improvement from previous formulations, where the barium selenate is prone to caking and clumping. TABLE 2 Batch # T1 295 Batch # T1 296 Batch # T1 297 Test Specification Initial 6 month @ Initial 6 month @ Initial 6 month @ 40*C175%RH 40*c/75%RH 40*C175%RH A pale yellow Description suspension with a Complies Complies Complies Complies Complies Complies characteristic odour Iodine 21.1 - 25.7%w/v 23.0 22.6 22.5 22.3 23.1 22.3 16 Selenium 2.25 - 2.75%w/v 2.37 2.27 2.33 2.49 2.38 2.25 Sterility Should comply Complies Complies Complies Complies Complies Complies Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.

Claims (17)

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% w/v 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 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. 18

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 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 (c) 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. 19

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 (c) mixing the mixture of step b) with micronised barium selenate powder; and, (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).

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