IE85851B1 - Parenteral formulation for the combined delivery of iodised unsaturated vegetable oil and barium selenate - Google Patents
Parenteral formulation for the combined delivery of iodised unsaturated vegetable oil and barium selenate Download PDFInfo
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- IE85851B1 IE85851B1 IE2009/0833A IE20090833A IE85851B1 IE 85851 B1 IE85851 B1 IE 85851B1 IE 2009/0833 A IE2009/0833 A IE 2009/0833A IE 20090833 A IE20090833 A IE 20090833A IE 85851 B1 IE85851 B1 IE 85851B1
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- Prior art keywords
- medicament
- oil
- iodised
- barium selenate
- iodine
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- 239000000203 mixture Substances 0.000 title claims abstract description 64
- ZIGAPMSTBOKWRT-UHFFFAOYSA-L barium(2+);selenate Chemical compound [Ba+2].[O-][Se]([O-])(=O)=O ZIGAPMSTBOKWRT-UHFFFAOYSA-L 0.000 title claims abstract description 36
- 238000009472 formulation Methods 0.000 title claims abstract description 31
- 235000015112 vegetable and seed oil Nutrition 0.000 title claims abstract description 19
- 239000008158 vegetable oil Substances 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 78
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 27
- 239000011630 iodine Substances 0.000 claims abstract description 27
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 27
- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 22
- 239000011669 selenium Substances 0.000 claims abstract description 22
- 239000003921 oil Substances 0.000 claims abstract description 17
- 235000019198 oils Nutrition 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 18
- 239000005662 Paraffin oil Substances 0.000 claims description 15
- 235000019483 Peanut oil Nutrition 0.000 claims description 12
- 239000000312 peanut oil Substances 0.000 claims description 12
- 238000007911 parenteral administration Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 239000000080 wetting agent Substances 0.000 claims description 7
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 230000002335 preservative Effects 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- 239000001593 sorbitan monooleate Substances 0.000 claims description 6
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 6
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 6
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 3
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 3
- 235000019484 Rapeseed oil Nutrition 0.000 claims description 2
- 235000019498 Walnut oil Nutrition 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 239000010491 poppyseed oil Substances 0.000 claims description 2
- 235000012424 soybean oil Nutrition 0.000 claims description 2
- 239000008170 walnut oil Substances 0.000 claims description 2
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical group CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 claims 2
- 239000002904 solvent Substances 0.000 abstract description 30
- 239000006185 dispersion Substances 0.000 abstract description 4
- 235000013311 vegetables Nutrition 0.000 abstract 1
- 239000002480 mineral oil Substances 0.000 description 13
- 235000010446 mineral oil Nutrition 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- NWGKJDSIEKMTRX-AAZCQSIUSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 206010067997 Iodine deficiency Diseases 0.000 description 4
- 235000006479 iodine deficiency Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 3
- 241000283898 Ovis Species 0.000 description 3
- 229910052788 barium Inorganic materials 0.000 description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 229940093471 ethyl oleate Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000036912 Bioavailability Effects 0.000 description 2
- 206010018498 Goitre Diseases 0.000 description 2
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine zwitterion Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 2
- 210000001165 Lymph Nodes Anatomy 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000023298 conjugation with cellular fusion Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 201000003872 goiter Diseases 0.000 description 2
- 230000013011 mating Effects 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- 230000021037 unidirectional conjugation Effects 0.000 description 2
- 241000238876 Acari Species 0.000 description 1
- 240000000800 Allium ursinum Species 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000011331 Brassica Nutrition 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 208000010515 Dystocia Diseases 0.000 description 1
- 210000001161 Embryo, Mammalian Anatomy 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 210000002149 Gonads Anatomy 0.000 description 1
- 210000002216 Heart Anatomy 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 201000009672 Keshan disease Diseases 0.000 description 1
- 210000004324 Lymphatic System Anatomy 0.000 description 1
- 208000004396 Mastitis Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 206010028302 Muscle disease Diseases 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 210000004165 Myocardium Anatomy 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- 208000008425 Protein Deficiency Diseases 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 229940034208 Thyroxine Drugs 0.000 description 1
- 210000002268 Wool Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 230000003628 erosive Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000009313 farming Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000032686 female pregnancy Effects 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002475 laxative Effects 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 229950008325 levothyroxine Drugs 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000003071 parasitic Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 231100000803 sterility Toxicity 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/18—Iodine; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
Abstract
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 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 iodised unsaturated vegetables oil barium selenate.
Description
PATENTS ACT, 1992 /0833 PARENTAL FORMULATION FOR THE COMBINED DELIVERY OF IODISED UNSATURATED VEGETABLE OIL AND BARIUM SELENATE BOMAC RESEARCH LIMITED PARENTAL FORMULATION FOR THE COMBINED DELIVERY OF IODISED UNSATURATED VEGETABLE OIL AND BARIUM SELENATE TECHNICAL FIELD The invention relates to an improved medicament formulation for the combined delivery of iodised unsaturated vegetable oil and barium selenate.
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.
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 closes 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.
Iodine is an essential element required by the thyroid gland for the manufacture of hormones thyroxine (T4), and tri-iodothyronine (T3). 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 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.
One widely used and long acting iodine medicament is Flexidinew 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 linoieic). 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 iengthy duration.
Selenium is an essential component of many enzymes which have broad ranging functions. Deficiency of selenium is associated with many conditions and diseases such as white muscle disease, cystic ovaries, early and late embryo death, mastitis and increased somatic cell counts, and Keshan disease (or cardiac muscle degeneration). lRT"' also manufactured by Bomac A long acting selenium medicament is Depose Laboratories Ltd. Deposelfim 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 Flexidinem, Deposelm“ provides a source of selenium to a treated animal for over approximately 12 months. One disadvantage of DeposelRT"' is that the medicament may be associated with adverse site reactions such as irritation and scarring. A further problem with the DeposelR"" 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 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 Plusm which administered both of the barium selenate and iodised peanut oil used in Depose|RTM and Flexidinem 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 Flexidinem and Deposelmm 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 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.
Further aspects and advantages of the present invention will become apparent 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) paraffin oil.
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) paraffin oil.
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 medicament including: (a) iodised unsaturated vegetable oil; (b) micronised barium selenate; and, (c) paraffin oil.
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) 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.
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) 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.
Previously, the applicants disclosed a combination formulation which included both iodised unsaturated vegetable oil and micronised barium seienate. This break- 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 invention was to provide a combination medicament which was substantially improved compared to simply mixing the Flexidinem and the active of Deposelm” together. However, the formulation medicament was still susceptible at times to clumping and caking of the barium seienate 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 seienate.
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.
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 clumpingl 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 types 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 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 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 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 Flexidinem and Depose|RT”' formulation (Flexidine PlusT"') is often slightly cloudy, yet is still effective and safe for use. Therefore, providing a combination Flexidinem and Deposelm formulation that does not have this cloudy or clumpy/cakey appearance may behighly 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 intended for this combination medicament.
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 N-alkanes, naphthenic oils based on cycloalkanes, aromatic oiis, based on aromatic hydro carbons.
Preferably the mineral oii 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 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 original suspension.
Preferably, the lipophilic oily solvent is approximately between 5-30% wlv 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.
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 esters, may be suitable for the current application.
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 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 Flexidinem 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 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 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 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 oil, micronised barium selenate, benzyl alcohol and sorbitan mono-oleate.
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 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 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; > 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 administered.
It is further envisaged that the medicament from the preferred embodiment may provide approximately 195 mg of iodine per ml of medicament administered.
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 to) 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.
Preferably, nitrogen gas is bubbled through the mixture of step d).
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 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 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 preferabiy 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 solvent) would not be obvious, othenivise this type of solvent would surely have been tested and applied previously through the applicant's investigations.
BRIEF D_ESCRIPT|ON OF QEAWINGS Further aspects of the present invention will become apparent from the ensuing description which is given by way of example only and with reference to the accompanying tables 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 includes a lipophilic oily solvent. gssr Megs FOR CA_RRY|NG our TI-lg Iuvguricm TABLE 1 Below is the applicant's preferred formulation which utilises mineral oil (paraffin oil) as the lipophilic oily solvent.
TABLE 1 Si no Ingredients %w!v 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 Liquid paraffin, heavy qs 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.
. Mix the required amount of benzyi alcohol with sorbitan monooteate and mix (approximately 15 minutes). Then add to the required iodised peanut oil.
. Mix till it is clear (approximately 20 minutes).
. Add and suspend the micronized barium selenate powder to the bulk. Stir to assure good suspension (approximately 50 minutes).
. Add the paraffin oil and make to the volume. Mix well (approximately 15 minutes).
. Homogenise the bulk using high shear homogeniser to get a smooth homogeneous suspension (approximately 15 minutes).
. Pack and purge nitrogen gas in the appropriate container.
TABLE 2 Table 2 provides the results from a six month stability analysis of a formuiation 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 six months. This is a significant improvement from previous formulations, where the barium selenate is prone to caking and clumping.
Iodine 21.1 — 25.7°/owlv 23.0 22.6 22.5 22.3 23.1 22.3 Selenium 2.25 - 2.75%w/v 2.37 2,27 2.33 2.49 2.38 2.25 Sterility Should comply Complies Com plies Complies Complies Complies Complies
Claims (17)
1. A medicament formulated for parenteral administration, wherein the medicament includes: (a) iodised unsaturated vegetabie 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% wlv 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 % wlv 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 ciaims 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. 17
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 vegetabie 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 bubbied through the mixture of step (d).
17. A medicament substantially as herein described with reference to Table 1 of the specification.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZNEWZEALAND31/10/2008572491 | |||
NZ572491A NZ572491A (en) | 2008-10-31 | 2008-10-31 | Composition for prevention and treatment of iodine and selenium deficiency |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20090833A1 IE20090833A1 (en) | 2011-03-30 |
IE85851B1 true IE85851B1 (en) | 2011-09-14 |
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