WO2003086375A1

WO2003086375A1 - Delivery systems for biologically active agents

Info

Publication number: WO2003086375A1
Application number: PCT/EP2003/003351
Authority: WO
Inventors: Cees Vermeer
Original assignee: Vitak Bv
Priority date: 2002-03-28
Filing date: 2003-03-28
Publication date: 2003-10-23
Also published as: AU2003219121A1

Abstract

Vitamins, bioactive compounds or trace elements are supplemented to cosmetic preparations such as lubricants, ointments, creams, body lotions, or lipsticks, and the like, in concentrations not only meant for skin care, but in quantities that will significantly increase their circulating concentrations. Compounds to be added to said dermal applications have a known preventive effect to the development of chronic diseases, or are deficient in a substantial part of the target group. The dermal applications form a carrier for transdermal transport. In that way a new product line is created by this invention which will contribute to preventive medicine and will benefit, amongst others, 10 populations which are difficult to reach and/or not easily motivated to take regular food supplements or functional food.

Description

DELIVERY SYSTEMS FOR BIOLOGICALLY ACTIVE AGENTS

Field of the invention

The present invention is in the field of organic chemistry, biochemistry, health sciences, cosmetics, and medicine. In particular the invention relates to a new concept for delivery of essential vitamins and trace elements to humans and animals to counteract deficiencies and to prevent chronic diseases.

Background of the invention Vitamins and trace elements are generally supplied to humans and animals through the oral route, whether or not in case of deficiency or as a maintenance dose, for example in foodstuff, food supplements, functional foods, or as pharmaceutical preparations. Drawbacks of delivering vitamins and trace elements via these products are, for example, that (1) only part of the population (notably those who are focused on health) is reached, (2) the products are not useful for subjects with malabsorption problems (such as obstructive jaundice, chronic pancreatitis, cystic fibrosis), and (3) oral intake of these products causes strong fluctuations in the circulating vitamin and trace element concentrations. The latter problem may be partly solved by slow release capsules, which are available for instance for vitamin C.

Three typical examples of such (sub)clinical deficiencies will be given below which are still widespread among large parts of the population, and for which the availability of oral supplements is insufficient to overcome the deficiency. This is not because oral supplements would not be active, but because a substantial part of the population does not take these supplements for whatever reasons.

The first example refers to vitamin K which is the cofactor for the endoplasmic enzyme γ-glutamyl carboxylase. The latter enzyme is involved in the formation of the unusual amino acid γ-carboxyglutamate in a limited number of proteins, including blood coagulation factors, and proteins regulating bone and calcium metabolism. Vitamin K deficiency to a level at which blood coagulation is disturbed is not seen in the healthy population. However, higher vitamin K intakes are required for optimal bone and vascular health. It has been reported that a substantial part of the western population may be subclinically vitamin K deficient [Booth, S.L. et al, J. Am. Diet. Assoc. 96 (1996) 149-154], especially in the light of the increased dietary reference intake levels for vitamin K (120 microgram per day for adults). Low vitamin K intake has been associated with enhanced postmenopausal bone loss and increased fracture risk [Feskanich, D. et al., Am. J. Clin. Nutr. 69 (1999) 74-79; Szulc, P. et al., Bone 18 (1996) 487-488; Knapen, M.H.J. et al., Calcif. Tissue Int. 63 (1998) 375-379] and with increased risk for atherosclerosis [Jie, K.- S.G. et al., Atherosclerosis 116 (1995) 117-123] and arterial calcification [Schurgers, L.J. et al., Z. Kardiol. 90:Suppl. 3 (2001) III/57-III/63]. Both calcification of atherosclerotic lesions at the site of the tunica intima as well as arterial hardening due to mineral deposition around the elastic lamellae in the tunica media may be counteracted by increasing a subject's vitamin K status. The second example refers to folates and folic acid, which are important factors in preventing neural tube defects in the developing fetus [Creizel, A.E. and Dudas, I. N. Engl. J. Med. 327 (1992) 1832-1835]. Without taking food supplements it is difficult to reach the Dietary Reference Intakes for folates, especially for pregnant women. This is the case in western society, but even the more so in developing countries. Moreover, folates are especially effective in preventing neural tube defects if supplementation starts before conception of the child. In the USA the incidence of neural tube defects was decreased by at least 10-fold after all cereal grain products had been fortified with 1.4 micrograms/g of folic acid. Folic acid has also a well-recognized beneficial effect on cardiovascular disease because it decreases circulating homocysteine levels [Brouwer, I A, et al., Am. J. Clin. Nutr. 69 (1999) 99-104]. It is difficult to obtain the required daily amounts from the diet alone, however.

The third example refers to vitamin A-deficiency, a well-known cause of blindness in developing countries, notably in south-east Asia and southern Africa [Gilbert, C, and Foster, A., Bull. World Health Organ. 79 (2001) 227-232; Ahmed, F., Public Health Nutr. 2 (1999) 1-14]. Neither food supplements nor food fortification programs reach these populations sufficiently, and complementary measures should be developed to decrease the incidence of vitamin A-deficiency induced blindness.

It is clear from these examples that the functional foods and food supplements which are available today have not resulted in full coverage of those suffering from vitamin insufficiency and that other ways of delivery are needed to improve the vitamin status of the population.

The present invention aims to provide such an improved delivery system. Summary of the invention In accordance with one aspect of the present invention, vitamins, bioactive compounds or trace elements are supplemented to cosmetic compositions that allow an effective increase of their circulating concentrations. According to another aspect of the invention cosmetic compositions are provided which are capable of transporting the above substances transdermally.

According to a further aspect of the invention preferred compositions of the cosmetic products are such that they combine optimal skin care with systemic disease prevention. According to a further aspect of this invention special product lines are provided for defined target groups including, but not limited to, elderly women for prevention of bone loss and cardiovascular disease, and young women for increasing their folate status before they become pregnant.

According to another aspect of the invention a cosmetic or skin care product composition is provided characterised in that it comprises at least one compound selected from the group consisting of vitamins, trace elements, and other biologically active elements (such as lipids, peptides, herbal extracts) in a concentration so as to effectively increase its circulating (systemic) concentration.

According to a further aspect of the invention the use of cosmetics and other skin care products is provided as a carrier for vitamins, trace elements and other biologically active compounds.

According to still another aspect of the invention the of at least one of a vitamin, trace element or other biologically active element is provided in the manufacture of a medicament or other formulation for topical use to effectively increase the systemic concentration of said one of a vitamin, trace elements and biologically active compound.

These and other aspects of the present invention will be elaborated further in the detailed description below.

Brief description of the drawings Figure 1 shows graphically a vitamin K analysis at t = 0 and 5 days of application (3 times daily). Arrows indicate 1 : MK-4 (absent in non-treated subjects), 2: vitamin K1 (variable, depending on previous meal), 3: Internal Standard. Detection of vitamin K was performed according to standard procedures after extraction of serum with hexane, pre-purification on a silica column, followed by HPLC analysis on a C-18 reversed phase column and fluorimetric detection after post-column reduction on a zinc column.

Figure 2 shows chromatograms for MK-4 uptake from lipophylic cream at t = 0, 8, and 24 h. Identification of peaks from right to left: internal standard, vitamin K1 , MK-4 (only in the upper curve) and front peak. The large peak at 24 h for MK-4 demonstrates that the skin can be used as a slow release system for systemic vitamin delivery.

Figure 3 shows chromatograms for MK-4 uptake from hydrophylic cream at t = 0, 4, 8, and 24 h. Identification of peaks from right to left: internal standard, vitamin K1 (very small), MK-4 (only in the upper curve), and front peak. The peak at 24 h for MK-4 demonstrates that also with hydrophylic creams the skin can be used as a slow release system for systemic vitamin delivery, but the data suggest a lower efficacy than with lipophylic creams.

Detailed description of the invention

As used herein, the term "cosmetic composition" or "cosmetic preparation" both means to indicate any product which is commonly used for skin care, such as ointments, creams, body lotions, lipsticks, and the like, as well as other lubricants, solvents, fats, detergents, and the like, which can be applied dermally.

Dermal application of drugs to humans and animals is a well known principle. For example, the topical application of estrogen in postmenopausal women demonstrates that estrogens are taken up by the skin and reach the circulation to prevent systemic complaints and diseases. Also, the use of vitamins in creams and body care products to improve the skin vitality and quality is known.

The present invention is based on the surprising discovery that menaquinone- 4 (a form of vitamin K2) was able to reach the circulation after topical application in the form of a hydrophilic cream. In high dosages (45 milligrams/day) the same form of vitamin K was shown to almost completely protect elderly women against postmenopausal bone loss after oral supplementation [Orimo, H., et al., J. Bone Miner. Metab. 16 (1998) 106- 112]. Also other vitamin K supplements and lower dosages (200 micrograms/day) were shown to improve bone mass [Bolton Smith, O, et al., Ann. Nutr. Metab. 45(suppl.) (2001) 46]. Oral administration of vitamin K results in a sharp increase of circulating vitamin K with a maximum around 4 h postprandially and a rapid decline with a half-life time of about 1.5 h [Schurgers, L.J., Vermeer, C. Haemostasis 30 (2000) 298-307]. Even at relatively high vitamin K intakes this results in sub-optimal plasma concentrations during part of the day. Menaquinone-4 (MK-4) is one of the more hydrophilic K-vitamers, but also has the shortest plasma and tissue half-life time. In an experiment detailed below oil- solubilized MK-4 was mixed with a hydrophilic cream resulting in a homogenous preparation which was applied on the skin. Although the increase of the circulating MK-4 concentration was much slower than after oral administration, the vitamin remained detectable at 24 h after dermal application. This experiment demonstrates, therefore, that the skin is able to form a slow-release system to bring biologically active compounds in the circulation and thus contribute to disease prevention.

Accordingly, the present invention provides compositions, preferably in the form of cosmetic and/or skin-care dermal compositions, comprising at least one of a vitamin, bioactive compound or trace element and a suitable carrier, wherein said vitamin, bioactive compound or carrier is in a concentration such that, when applied to the body, it will reach the circulation in an effective amount and will contribute not only to dermal care, but also to total health care. The present invention can be employed in a variety of ways by administering at least one benefit agent selected from the group consisting of vitamins, bioactive compounds and trace elements through incorporation in a cosmetic preparation for topical use, such as, for example, a cream, body lotion or lipstick. Vitamins which can be suitably employed in the compositions according to the invention include, but are not limited to vitamins A, E and K. Bioactive compounds which can be suitably employed in compositions according to the invention include, but are not limited to folic acid, lipoic acid, and ubiquinone. Trace elements which can be suitably employed in compositions according to the invention include, but are not limited to liposomes, (poly)unsaturated fatty acids, and minerals. According to one embodiment of the invention vitamin K is incorporated in a cosmetic preparation in an effective amount so as to be taken up by the skin and to reach the circulation to exert its beneficial therapeutic or prophylactic activity. Since it is expected that notably elderly subjects will benefit from an increased vitamin K status, they form a special target group at which a special product line is aimed both by marketing as well as by its specific characteristics (smell, colour, etc.). Systemic diseases that are likely to be prevented or retarded by vitamin K are osteoporosis and arterial sclerosis (hardening of the vessel wall or calcification of the atherosclerotic plaque). In this respect it is noteworthy that (1) arterial calcification initiates around the elastic lamellae of the tunica media, (2) the vitamin K-dependent protein MGP is especially expressed and accumulates around these elastic fibers, and (3) in experimental animals vitamin K-deficiency was shown to result in rapid calcification of the elastic lamellae [Price, P.A. et al., Arterioscler. Thromb. Vase. Biol. 18 (1998) 1400-1407]. In the skin, elastic fibers occur which are histochemically very similar with those found in the vasculature. After calcium deposition around these fibers, they degrade into smaller fragments, which is supposed to be the direct cause of reduced elasticity. The calcification inhibiting vitamin K-dependent protein MGP is also produced in skin, and local vitamin K-insufficiency will likely result in the destruction of elastin fibres and skin ageing. The close similarity between the elastic fibres in arteries and skin makes likely that dermal use of vitamin K is also important for the maintenance of skin elasticity.

According to another embodiment of the invention folic acid is incorporated in a cosmetic preparation in an effective amount so as to be taken up by the skin and to reach the circulation to exert its beneficial therapeutic or prophylactic activity. This embodiment is especially useful for increasing the folic acid status in women of child- bearing age, thus preventing the risk of neural tube defects. This will require a completely different product line and marketing, specifically aimed at younger women, maybe even differentiated between women in the western society and those in Asia or Africa. Also the optimal carrier for transdermal folic acid application may be different from that used for vitamin K. The additional aspect of lowering circulating homocysteine and thus decreasing the risk of cardiovascular disease may be a stronger argument in western society than elsewhere. In this respect it is noteworthy that a polymorphism has been found in the enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) affecting the folate status [Molloy et al., The Lancet 349 (1997) 1591-1593]. The mutation leads to thermolability of MTHFR and increased levels of homocysteine. About 5-15% of the general population are homozygous for this variant, which causes mild hyperhomocysteinemia and is positively associated with the development of neural tube defects in the fetus and with coronary artery disease in adults. Another beneficial effect of increasing the folate status may be the reduction of colorectal cancer. Folate deficiency causes massive incorporation of uracil into human DNA, which will likely result in the initiation of neoplastic transformation [Blount, B.C., et al., Proc. Natl. Acad. Sci. USA 94 (1997) 3290-3295].

According to still another embodiment of the invention vitamin A is incorporated in a cosmetic preparation in an effective amount so as to be taken up by the skin and to reach the circulation to exert its beneficial therapeutic or prophylactic activity. This embodiment is of particular use in populations with a high incidence of vitamin A deficiency-induced blindness. Such blindness occurs both in children and adolescents, as well as in adults. In many cases regular supplementation of vitamin A capsules or tablets fails because of ignorance. Therefore, genetically modified rice has been developed ("yellow rice") in which vitamin A is expressed spontaneously. An alternative way of administration according to the present invention is, for instance, through a special lipstick containing vitamin A. Irrespective whether the vitamin is absorbed in the skin, a small part will reach the digestive tract via the oral route, thus preventing vitamin A deficiency.

According to still a further embodiment the compositions of the present invention can be suitably used for administering medication to a human or animal which is not well tolerated by the gastro-intestinal tract, in particular when the medication is intended for treating chronic diseases. Examples of such medications include the treatment of rheumatoid arthritis or an oral anti-coagulation therapy in which high and low dosages of acetylsalicylic acid are administered, respectively, over a long period of time. Another example is the treatment of osteoporosis with bisphosphonates over a long period. These medicines frequently cause serious stomach problems which can be avoided by the present compositions.

The compositions according to the present invention can be suitably applied to humans, of any age, and animals. When the compositions are used to animals, they are preferably used to pets (cats, dogs, hamsters, etc.), but they can also be used to other animals, for example horses, cattle, sheep, goats, porcines, etc.

It will be understood by a person skilled in the art that the optimum carrier for the vitamins and trace elements to be administered topically according to the present invention will depend on various factors, such as the specific compound(s) to be supplemented, which compounds may differ widely with respect to properties such as hydrophilicity, charge and size. In certain case, for example when applying hydrophobic substances such as vitamins E and K as active ingredient, an emulsifier (e.g. a detergent) and/or a liposome is optionally included in the carrier product. Other factors that will influence the type of product used for topical administration of said compounds include local habits and fashion, as well as the target group(s), at which a certain product is aimed. Specific target groups may be defined according to age, gender, socio-economic status, geographic localisation, or race. Therefore, the composition of the carrier cosmetic product generally will have to be adapted for each purpose. However, a person skilled in the art will have no difficulty in making the appropriate selections without undue experimentation, based on his skill and knowledge, and on the teaching of the present invention. Of course, a skilled person will also be able to determine and optimize the appropriate amounts and proportions of the ingredients of choice to reach the desired effect without inventive effort

The present invention is further illustrated by the following examples which, however, should not be construed in any respect as a limitation of the invention.

Experimental

In the experiments described below menaquinone-4 (MK-4, one of the K2 vitamins) was taken as an example because in non-supplemented individuals this form of vitamin K is not detectable in the circulation. In a number of experiments MK-4 was added to creams, applied daily at a fixed area of the upper arm and MK-4 was analyzed in the blood stream on subsequent days.

Example 1 In this experiment oil-solubilized MK-4 was homogenized in a pH neutral cream on a basis of liposomes (0.1 mg MK-4 / g of cream), and the right fore arm of the test subjects was embrocated three times with 5 g of cream: at 7.00 am, 6 pm, and 11 pm. during four successive days. Venous blood samples were taken from the left arm (to circumvent contamination) at baseline, and on the morning of day 5. The serum MK-4 concentration was assessed according to well-established techniques [Schurgers, L.J., Vermeer, C. Haemostasis 30 (2000) 298-307]. Baseline and t = 5 days measurements are shown in Figure 1 , with a clear peak of MK-4 visible. This peak is much lower than what would have been obtained during the first hours following a similar amount of oral MK-4 ingestion, but the fact that it is visible at 10 h (overnight) after the last application demonstrates that the skin functions as a slow release system for essential vitamins and trace elements.

Example 2

Five different basic creams varying from lipophylic to hydrophylic were used as a starting material. MK-4 powder was added to the creams to a concentration of 1 mg/g of cream. Five volunteers were included, and each volunteer used one cream. The creams used were commercial base preparations for mixing active ingredients: lanette (hydrophylic), cetomacrogolis (hydrophylic), unguentum leniens (intermediate), vaselini with PCH (lipophylic), and vaselini cetomacrogolis (lipophylic). The lipophylic creams showed the highest uptake, also uptake was at its maximum within 2 days. The creams were applied to the right upper arm twice daily, serum samples were taken at days 0, 2 and 4 and circulating concentrations of MK-4 were assessed. The data are summarized in table 1 below. Table 1

Example 3

Oil-solubilized MK-4 (as in Example 1) was added to one lipophylic cream (vaselini with PCH) and to one hydrophylic cream (cremor cetomacrogolis). The concentration used was 0.72 mg of MK-4 per gram of cream. At t = 0 a blood sample was taken and one single portion of 1.5 g of cream was applied at the upper right arm. Further blood samples were taken at t = 4, 8, and 24 h. The data are summarized in table 2 below and in Figures 2 and 3. Table 2

Time curve for MK-4 uptake from two different creams

These experiments clearly show that the skin can be used as a slow release system for delivery of vitamins from cosmetic preparations such as creams. Lipophylic creams are preferable in this respect, although also hydrophylic creams can also be used. Application once or twice daily will ensure constant blood levels and these levels can be reached within 24 hours. Therefore, the use of vitamins and other micronutrients in creams and other cosmetic topical preparations according to the present invention provides an added value to creams and cosmetics with a beneficial effect for the skin.

Claims

1. A cosmetic composition characterised in that it comprises at least one compound selected from the group consisting of vitamins, trace elements, and other biologically active elements in a concentration so as to effectively increase its circulating (systemic) concentration.

2. Use of a cosmetic composition as a carrier for vitamins, trace elements and other biologically active compounds.

3. Use of at least one of a vitamin, trace element or other biologically active element in the manufacture of a medicament or other formulation for topical use to effectively increase the systemic concentration of said one of a vitamin, trace elements and biologically active compound.

4. Use of at least one of a vitamin, trace element or other biologically active element in the manufacture of a medicament or other formulation for topical use as claimed in claim 3, to prevent, retard, or decrease the risk of chronic diseases such as osteoporosis and atherosclerosis.

5. Use of at least one of a vitamin, trace element or other biologically active element in the manufacture of a medicament or other formulation for topical use as claimed in claim 3, to prevent deficiency-related diseases such as neural tube defects and vitamin A-related blindness.

6. Use of at least one of a vitamin, trace element or other biologically active element in the manufacture of a medicament or other formulation for topical use as claimed in any one of claims 3 to 6, characterised that said medicament or said other formulation further comprises a vehicle which is capable of easily penetrating the skin.

Use of a composition as claimed in claim 1 in combination with other ingredients to optimize skin care and to prevent skin ageing.