AU2014101500B4 - Vitamin D3 Oral Spray - Google Patents

Abstract

The present invention provides a liquid, orally deliverable vitamin D composition, comprising non-animal derived vitamin D3, present as cholecalciferol, or a salt thereof, in an amount of about 501U to about 20001U per dose, in a pharmaceutically acceptable excipient, wherein the composition is substantially free of artificial preservatives. The invention also provides methods of treating or preventing a disease or condition associated with vitamin D deficiency in a human subject and methods for supplementing a subject's vitamin D intake.

Description

1 VITAMIN D3 ORAL SPRAY FIELD OF THE INVENTION [0001] The invention relates to a low dose, oral delivery, liquid vitamin D3 composition, wherein the vitamin D3 is not animal derived. The invention also relates to the use of the composition in the treatment of vitamin D deficiencies. BACKGROUND TO THE INVENTION [0002] Vitamin D deficiency has long been recognised as a significant medical condition. It was established many years ago that it lead to the bone diseases osteomalacia in adults, and rickets in children. Subsequent research has shown that vitamin D is crucial for the absorption and metabolism of calcium and phosphorous, and in bone mineralisation, tooth development and cell growth generally. More recently vitamin D deficiency has been implicated in a range of other disease conditions including food allergy, immune function, cancer, multiple sclerosis, tuberculosis, cardiovascular disease, infectious diseases and cognitive ability. [0003] Vitamin D deficiency can be caused through poor nutrition and a lack of sun exposure. In the context of a changing Western lifestyle, both of these above causes are becoming more evident. [0004] With an increasing number of persons adopting a vegetarian/vegan diet, the lack of animal protein can result in reduced serum levels of the active forms of vitamin D, calcidiol, also known as 25-hydroxycholecaliferol or 25-OHD (= 25 hydroxy vitamin D), and the two principal metabolites calcitriol, also known as 1, a, 25-dihydroxy vitamin D3, and 24,25-dihydroxy vitamin D3. [0005] Compounded with our increased sedentary lifestyle, more people working indoors, demands for increased workplace productivity, with more people 2 working night shifts, and the very successful campaign to use sunscreen, to limit sunburn and decrease the high rates of melanoma in Australia, there is now an increasing incidence of persons suffering vitamin D deficiency caused through a lack of sun exposure. The blocking effects of sunscreens, especially their ability to block ultraviolet B radiation, cannot be underestimated. Even low value sun protection factor sunscreens (e.g. SPF 15) can have a very significant effect on in vivo vitamin D synthesis. One study suggests that SPF 15 can limit a person's synthetic capacity to produce vitamin D by 98%. [0006] It is now estimated that one third of Australians suffer from vitamin D deficiency. But this problem is not limited to Australia. Vitamin D deficiency it is a world wide problem, from the upper latitudes of the Northern hemisphere (where long winters result in limited sun exposure for many months) through to the Middle East where environmental, social and cultural factors, mean the population remains indoors during the day and have whole-of-body clothing conventions. [0007] It is also important to recognise that vitamin D in large doses (generally achieved by overdosing on supplements) can be toxic, and result in hypercalcemia, and hypercalcuria, leading to kidney calcification/renal disease, and anorexia. [0008] Current recommendations for treating moderate to severe vitamin D deficiency include supplementing a person's daily intake of vitamin D by administering between 3000 - 50001U of vitamin D per day for between 6 to 12 weeks, with an ongoing dosage of between 10001U - 20001U per day for another 6 to 12 weeks. [0009] Whilst vitamin D supplements are readily available, most of the vitamin D3 products are animal based, with lanolin being a major source. Some vitamin D products use vitamin D2 (ergocalciferol) derived from yeast, which are suitable for vegetarians and vegans. However, there is debate about the 3 biological efficacy of vitamin D2 supplements, compared with vitamin D3 supplements, given their respective metabolic processing. [0010] In terms of excipients for oral delivery of vitamin D, there are many oils available for use in complementary medical supplements. All have similar levels of energy and omega essential fatty acid profiles. Examples include soybean, corn, canola, cottonseed, safflower, rice bran, olive and coconut oils. Each have their own particular advantages and uses, but there exist concerns about oils derived from genetically modified crops so this potentially limits the available options. [0011] It is desired to provide a vitamin D3 composition that can be used in treating / preventing vitamin D deficiency, or supplement a person's vitamin D intake, particularly for special target populations such as vegetarians/vegans, or those who do not have sufficient sun exposure, and at the same time avoiding a possible overdose and stimulating an allergic reaction. [0012] It is an aim of the invention to provide a low dose vitamin D3 supplement that can be delivered orally and is stable in solution. A further aim is to provide a method of treating and/or preventing vitamin D deficiency, or supplementing a subject's vitamin D intake. SUMMARY OF THE INVENTION [0013] In a first aspect of the invention there is provided a liquid, orally deliverable vitamin D composition, substantially free of artificial preservatives, comprising: non-animal derived vitamin D3, present as cholecalciferol or a salt thereof, in an amount of about 501U to about 10001U per metered dose of approximately 180 to 200 pL, in a pharmaceutically acceptable oil-based excipient, having a gamma oryzanol and ferulic acid content adequate and sufficient to provide antioxidant and anti-microbiological functionality against degredation of cholecalciferol over a 24 month shelf-life of the composition.

4 [0014] The preferred non-animal derived vitamin D3 is sourced from a plant, or a Lichen species, through extraction or other methods employed in extraction of active compounds from plant or lichen raw materials. Lichen are organisms formed by the symbiotic association of a fungus and an algae or cyanobacterium. [0015] As noted, the preferred pharmaceutically acceptable excipient is rice bran oil, as it has excellent shelf-life and antioxidant stability. It is believed that amongst other chemical compounds present in rice bran oil (preferably unprocessed) the gamma oryzanol and ferulic acid molecule combination provides excellent antioxidant and anti-microbiological functionality in preventing degradation and microbiological attack of plant-sourced vitamin D3. [0016] Noting that there is a growing body of evidence that suggests that artificial colourings and preservatives, such as bisulphites and benzoates, may induce allergic reactions, in particular asthma, the vitamin D composition according to the invention dispenses with added preservatives, which are normally present in known high dose vitamin D supplements. [0017] It has been surprisingly found that despite the absence of added preservatives such as benzoates, bisulphites and similar preservatives used in pharmaceutical and nutraceutical compositions, physiologically relevant microbiological contamination of the composition is absent during the intended shelf-life of the composition, which is currently believed to be at minimum of 24 months, at the levels of inclusion of vitamin D3 in the composition. Without wishing to be limited by any particular scientific theory, the inventors believe that the antioxidant actives in rice bran oil protect the lichen-derived vitamin D3 from microbial degradation. [0018] Preservatives for use in liquid compositions in the pharmaceutical arts are well known, and in the context of the invention the composition of the first aspect is substantially free of preservatives. That is to say, it does not contain any added artificial preservatives. Particular preservatives that are excluded include 5 ethanol, glycerine or gycerols, benzoates, sorbates, sulphites, EDTA and salts thereof and parabens. Other artificial preservatives would be also known to the skilled addressee and these too are not used within the composition of the first aspect of the invention. [0019] There are many vitamin D3 supplements available for general over the counter sale/purchase by the general public. These supplements have a wide range of concentrations of vitamin D3, from 20001U to 50001U per mL. The typical daily dose is between 20001U to 50001U. Higher dosage forms are available from medical practitioners, and include dosage ranges of around 50,0001U. The recently published International Patent Application PCT/AU2010/001626 envisages dosages of up to 250,0001U per mL. [0020] However, these various supplements are provided in complex mixtures and include artificial preservatives, stabilisers and other undesired components. It is known that concentrated vitamin D compositions require stabilisers and antimicrobial additives, to prevent microbial spoilage, along with other additives such as flavours. Examples include Vitamin D3 in admixture with soy derived vitamin E, various fatty acids including mono and digylcerides, olive oil, sorbates, benzoates and vanilla flavour. [0021] In a second aspect of the invention there is provided a method of treating a disease or condition associated with vitamin D deficiency in a human subject, the method comprising orally delivering a therapeutically effective amount of the liquid vitamin D composition of the first aspect of the invention over a time frame until the subject's blood serum levels of the active forms of vitamin D are stabilised within predetermined health indicators.

5a [0022] In a third aspect of the invention there is provided a method of supplementing a subject's vitamin D intake, the method comprising orally delivering to a human subject a supplementally effective amount of the liquid vitamin D composition of the first aspect of the invention to maintain a desired blood serum level indicative of the normal range of vitamin D.

6 [0023] The route of oral administration is most effectively performed by delivery onto the sublingual portion of the mouth. This delivery mode is more efficacious than uptake through gastrointestinal uptake. It is believed that this increased efficacy is due to the concentration of blood vessels under the mucous membrane of the tongue, whereby the vitamin is directly absorbed into the venous circulation. This avoids the first pass metabolism process, wherein the vitamin is absorbed through the gastrointestinal tract and passes through the liver, where it can be modified to less effective molecular forms. [0024] The mode of oral delivery is preferably by administration of the vitamin D composition as a metered spray dose onto the sublingual region of the mouth, the preferred metered dose having a volume of around 200 mcL. [0025] In the context of the specification the following definitions may be helpful in understanding the invention. [0026] The term 'therapeutically effective amount' means providing a sufficient amount of a substance, that is non-toxic, to a subject to achieve the desired therapeutic effect. The term 'therapeutically effective amount' will be understood by the skilled addressee to include a range of amounts that will vary according to the condition to be treated, its severity and the health profile and status of the recipient subject. The exact amount to be administered would be able to be determined by the skilled addressee. [0027] Diseases or conditions (also known as indications for treatment/prevention) that would potentially benefit from being treated with the vitamin D3 composition of the invention are those where vitamin D deficiency is implicated or is overt. Such diseases and/or conditions include but are not limited to osteomalicia, rickets, bone mineralisation conditions, autoimmune diseases, cardiovascular and metabolic diseases, cancers such as colorectal, breast, prostate and colorectal adenoma, diabetes, tuberculosis and other infectious diseases and some neurological and mental health conditions.

7 [0028] In a preferred embodiment the particular indications for treatment with the vitamin D3 composition of the invention include assisting calcium absorption, support of baby growth during pregnancy, maintaining serum calcium and phosphorous levels and supporting bone density [0029] In an even further preferred embodiment there is a provided a method of supplementing a subject's vitamin D intake, the method comprising delivering a supplementally effective amount of a vitamin D composition comprising non-animal derived vitamin D3, present as cholecalciferol, or a salt thereof, in an amount of about 501U to about 10001U per dose, in a pharmaceutically acceptable excipient, particularly rice bran oil, wherein the composition is substantially free of artificial preservatives. [0030] In a further embodiment, the method of supplementing a subject's daily intake of vitamin D using the vitamin D3 composition of the invention is particularly useful for subjects whose exposure to sunlight is such that they do not synthesize sufficient endogenous vitamin D. [0031] Advantageously, the supplementation of a subject's vitamin D level is such that the subject's serum vitamin D levels (measured as circulating serum 25-OHD) is above 50nmol/L at the end of winter, or 10-20 nmol/L at the end of summer, in order to provide optimal musculoskeletal health. [0032] Preferably, in supplementing a subject's daily intake of vitamin D, particularly in subjects whose daily sunlight exposure is minimal, the composition is administered to provide at least 600 to 8001U vitamin D3daily. DESCRIPTION OF PREFERRED EMBODIMENT [0033] The present invention will now be described with reference to the following examples, which should not be construed in any way as limiting the scope of the invention.

8 [0034] Example 1: A vitamin D3 composition containing 1 0001U per dose. [0035] An example of the vitamin D3 composition of the invention, as calculated for a 50mL dispensing batch (containing 277 doses per bottle), has the following make up: Component Amount per mL Amount per 50mL Vitamin D3 (as 55401U 55,400 cholecalciferol) (Calculated as 10001U per 6.9mg dose = 25mcg/ 180.5mcL = 0.138mg/mL) Rice bran oil 912.6 mg/mL 45.63g [0036] A 180.5mcL dose contains: 25 mcg (10001U) Vitamin D3, as cholecaliferol and 164.72 mg rice bran oil. [0037] The vitamin D3 raw material (Vitashine, Nottingham, United Kingdom) is provided as a concentrate. When diluted to make the orally deliverable composition it includes a final concentration of 0.00617mg/mL of D-a tocopherol (Vitamin E) as an antioxidant, and 6.00mg/mL of vegetable oil. [0038] A vitamin D3 composition of Example 1 was subject to stability and microbiological testing. The product of Example 1 presents as a clear to pale yellow liquid, and has a shelf life of 2 years when stored at 250 C and complies with the BP (British Pharmacopeia).

9 [0039] Microbiological testing of the starting materials, and final batch product of a composition as described in Example 1, yielded the following results: Test Result TVA Count NMT 10,000 cfu/g Yeast and Mould Count NMT 100 cf u/g Bile-Tolerant Gram-negative bacteria NMT 100 E.coli Detection Not detected /g Salmonella Detection Not detected /1 Og Staphylococcus aureus Not detected /g [0040] Example 2 - Stability Testing at 6 Months [0041] A vitamin D3 composition of similar composition to Example 1 was subjected to stability testing. [0042] In this example the concentration of cholecaliferol was approximately 0.178mg/mL, with a rice bran oil content of 912.59 mg/mL 10 [0043] The composition was stored at 250C, and 60% humidity for six months and then assayed for overall visual appearance, specific gravity and total cholecaliferol. [0044] The results are shown in Table 1. Test Method Initial 6 months Conducted Appearance Visual observation Clear pale yellow Clear pale free flowing liquid. yellow free flowing liquid Specific BP 0.92 0.92 Gravity (0.88 - 0.97) Cholecaliferol HPLC analysis 0.178mg/ml 0.182mg/ml (Vit D3) (154-183 mcg/ml) [0045] The above results show that a vitamin D3 composition of the invention is unexpectedly stable and shows no overt indications of chemical 11 breakdown or physical change after 6 months storage without the inclusion of any artificial preservatives. [0046] Example 3 - Preparation of a Vitamin D3 Composition [0047] A general method of preparing a vitamin D3 composition of the invention includes the following steps: (a) Raw materials, including the vitamin D3 base material (Vitashine, Nottingham, United Kingdom: containing cholecaliferol, D-a tocopherol and vegetable oil) and rice bran oil that have been pre screened, and microbiology tested, are selected; (b) Selected raw materials are dispensed into individual holding containers using a 3WS computerised production system (Wayahead Systems, Jersey City, NJ, United States of America) under GMP conditions. (c) The rice bran oil is mixed in a main tank for approximately 10 minutes to provide a homogeneous mixture; (d) The vitamin D3 base solution in then added and mixed until a uniform solution is achieved. (e) Additional rice bran oil is used to wash down the sides of the main tank and the solution is mixed until a uniform solution is achieved. The mixed solution is quality assurance tested before dispensing. (f) The mixed solution is then filtered into a holding tank and dispensed into 50mL white round HDPE bottles with a white fine mist spray cap. Individual shrink sleeves are applied to each bottle.

12 [0048] The skilled addressee would know and appreciate the types of mixing required to achieve mixtures of oil based admixtures as used in the composition of the invention.

Claims (5)

1. A liquid, orally deliverable vitamin D composition, substantially free of artificial preservatives, comprising: non-animal derived vitamin D3, present as cholecalciferol or a salt thereof, in an amount of about 501U to about 10001U per metered dose of approximately 180 to 200 pL, in a pharmaceutically acceptable, oil-based excipient, having a gamma oryzanol and ferulic acid content adequate and sufficient to provide antioxidant and anti-microbiological functionality against degredation of cholecalciferol over a 24 month shelf-life of the composition.

2. The vitamin D composition of claim 1, wherein the concentration of the vitamin D3 in the composition is in the range of about 6.9 pg/mL to about 25 pg/mL.

3. The vitamin D composition of claim 1, wherein the non-animal derived vitamin D3 is from a plant or lichen.

4. The vitamin D composition of claim 1, 2 or 3, wherein the excipient is rice bran oil.

5. The vitamin D composition of claim 4, wherein the rice bran oil is present in an amount of about 900 mg per mL composition. BIOMEDICA NUTRACEUTICALS PTY LTD WATERMARK PATENT AND TRADE MARKS ATTORNEYS UIP1482AU00