NUTRACEUTICAL COMPOSITION AND DOSING REGIMEN

Abstract

The present invention is a nutraceutical formulation, intended for oral administration, comprising co-administered if not co-formulated melatonin together with at least one of strontium, Vitamin D, and Vitamin K or their analogues. The nutraceutical combination or formulation is designed to be taken by mouth within about two hours prior to bedtime, and in fact should not be taken at any other time. The combination therapy gives new and unexpectedly improved results compared to the administration of melatonin alone.

Claims

1. A nutraceutical method of treating multiple indications relating to osteopenia and osteoporosis, comprising administering one time per day, within two hours of bedtime, at least one unit dose of melatonin combined with at least one dose of one of strontium, Vitamin D or Vitamin K or their analogues in an appropriate vehicle or dosage form for a human patient in whom such treatment is indicated.

2. The nutraceutical method of claim 1, wherein said strontium is a strontium salt, said Vitamin D is Vitamin D3, and said Vitamin K is Vitamin K2, and further wherein all four of melatonin, Vitamin D3, Vitamin K2 and a strontium salt are present in said nutraceutical.

3. The nutraceutical method of claim 1, wherein said unit doses are separate or combined in a dosage form suitable for oral administration.

4. The nutraceutical method of claim 1, wherein said unit doses are separate or combined in a dosage form suitable for parenteral, transmucosal, transdermal, or topical delivery.

5. The nutraceutical method of claim 1, wherein said unit doses are packaged in a kit, in which a separate dosage form containing calcium or calcium with and at least one form of Vitamin D is also present, prior to administration.

6. The nutraceutical method of claim 1, wherein said administration occurs daily for a minimum of six consecutive months.

7. The nutraceutical method of claim 1, wherein said administration occurs daily for a minimum of one year.

8. The nutraceutical method of claim 1 wherein, as a result of the administration, bone density, bone formation, in said post-menopausal woman increases and post-menopausal sexual function and interest also increase, compared to post-menopausal women who are not treated according to the method of claim 1.

9. A nutraceutical composition containing 0.1-20 mg melatonin, 0.1 mg to 3 g strontium (citrate), 0.1-10,000 IU vitamin D3 and 0.1-300 g vitamin K2.

10. (canceled)

11. A nutraceutical composition containing 5 mg melatonin, 450 mg strontium (citrate), 2000 IU vitamin D3 and 60 g vitamin K2.

12. A nutraceutical composition according to claim 11 wherein at least one pharmaceutically acceptable excipient is present in said composition.

13. A nutraceutical composition wherein a kit contains at least two separate dosage components forms for administration, a daytime kit component containing calcium, calcium and Vitamin D, or any other vitamin, mineral, herb, plant extract, fatty acid, or nutraceutical in any dosage and combination and a composition according to claim 9 for administration within two hours of bed time.

14. A nutraceutical composition according to claim 9 with the addition of any other vitamin, mineral, herb, plant extract, fatty acid, amino acid, or nutraceutical or food nutrient in any dosage and combination, with the exception of calcium.

15. The nutraceutical method of claim 1 wherein, as a result of the administration, metabolic function, in said post-menopausal woman improves compared to post-menopausal women who are not treated according to the method of claim 1.

16. The nutraceutical method of claim 1 wherein, as a result of the administration, diabetes risk, in said post-menopausal woman decreases compared to post-menopausal women who are not treated according to the method of claim 1.

17. The nutraceutical composition in kit form according to claim 13, wherein all compositions are formulated for oral administration.

18. A method of treating a patient at risk for low bone mass, bone loss, osteopenia and osteoporosis by administering, in unit dosage form, one or more dosages of the nutraceutical set forth in claim 1 on a daily basis.

19. The method according to claim 18 wherein said daily treatment continues for a period of at least six months.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0008] The invention is a specific method of nutraceutical supplementation in which prevention, reduction or treatment of osteopenia or osteoporosis or osteopenia is indicated, by administering a synergistic combination of melatonin with active supplement agents within two hours' time prior to bedtime. The dosing amounts set forth in the previous paragraph may be adjusted, according to the skill of the art, to accommodate patients whose body weights vary significantly from an average body weight. The active agents of the present invention, as well as their compounding and oral dosage form preparation generally, are already known in the art, and the present invention is directed to the improvement of co-administration of melatonin, strontium, Vitamin K2, and Vitamin D in the improved therapies disclosed herein. Suitable types and salts of strontium may be selected from the group consisting of, but not limited to, strontium citrate, strontium carbonate, strontium malate, strontium gluconate, strontium ascorbate, strontium glycinate, strontium chloride, strontium hydroxyapatite, strontium threonate or other strontium salts and combinations thereof. As described immediately above, the present nutraceutical combination or formulation is designed to be taken by mouth within about two hours prior to bedtime, and in fact should not be taken at any other time because of melatonin's nighttime circadium activity.

[0009] Prior to the present invention, studies have shown that sufficient sleep is important to the promotion of healthy sexual desire and genital response, as well as the likelihood of engaging in partnered sexual activity. These relationships were independent of daytime affect and fatigue. Unique to the present invention, in addition to improved results in preventing and treating osteoporosis and osteopenia, a new and surprisingly improved result, with the invention described herein, has been shown in that post-menopausal women who take the present nutraceutical composition every day within two hours' prior to bedtime, for a period of at least six consecutive months of consecutive daily doses, can expect a natural increase and return of sexual desire and function, compared to post-menopausal women who do not take the present nutraceutical supplement. This wellness improvement is a new and surprising benefit and, prior to the present invention, would clearly have been medically counterintuitive, as follows. Melatonin in general is so ubiquitously associated with bedtime and sleep enhancement that its ability to cooperate with other nutrients to improve sexual function would have seemed, prior to the present invention, to have suggested, Will this make me too sleepy for sexual activity? The inventors have discovered that the opposite is true. When post-menopausal women take the present nutraceutical as prescribed, daily and for at least six consecutive months, the favorable improvement in sexual desire increases, and without interfering or reducing the improvements in sleep quality attributed to melatonin, if taken as monotherapy. Daytime sleepiness did not increase as a result of the present invention, which is further indication of the promotion of sleep quality with an accompanied increase in sexual desire. The present invention describes for the first time the increased sexual desire (without need to wait until cessation of sexual activity for intake or other dosing) and the wellness effect of good overall sleeping and sleep schedules (going to bed on time, around 10 pm or so, and waking up on time, around 7 am or so) without napping or at least without napping too frequently. The clinical study results that led the inventors to the above conclusions, not only as to improved sexual function and desire in post-menopausal women on a chronobiology basis, but also as to the measurable improvements in their osteoblast (bone forming cells) formation, gave rise to the illustrative and descriptive memorable marketing characterization, Osteoblast Your Libido!, which according to the confirmed data in the present invention turns out to be literally true, as well as difficult to ignore.

[0010] Although the above described constituents are the most preferred, some substitution and combinations are possible with the inventive formulations with co-administrations with melatonin, in that any form of strontium or strontium salt or combination thereof may be used in the present invention as the strontium component. Likewise, any form of Vitamin D.sub.3, Vitamin D.sub.2 or Vitamin D analogs or combinations thereof may be used in the present invention as the Vitamin D component. Likewise, any form of Vitamin K.sub.2 (MK7), Vitamin K.sub.2 (MK4) or Vitamin K.sub.1 or Vitamin K.sub.3 or combinations thereof may be substituted in the present regimen for the Vitamin K constituent. Likewise, the suitable nutraceutical combinations can also consist of melatonin and strontium; melatonin, strontium and Vitamin D; or melatonin, strontium and Vitamin K. Likewise, the addition of any other nutraceutical ingredient without limitation, such as to include vitamins, minerals, amino acids, plant extracts, antioxidants, hormones, polyphenols, flavonoids, etc., may be used in the present invention with any of the suitable nutraceutical combinations. However, melatonin per se is a constant of the present invention; there is no ingredient that can substitute for melatonin, except for melatonin analogues and agonists.

[0011] Although the preferred route of administration of the present invention is oral, it is also possible to formulate and to administer the present constituents, for co-administration or as a co-formulation, via the routes of administration including transdermal, dermal using a topical lotion, gel or cream, transmucosal including vaginal, sublingual, buccal, pessary, etc., or parenteral. Adjusting dosing for these alternate-to-oral routes of administration is known in the art, and takes into consideration the ability of the constituent to bypass the hepatic first pass effect while also compensating for reduced delivery through the epidermis compared to mucosa, and so forth.

[0012] However, to simplify compliance, the combined active agents may desirably be compounded together in an oral dosage form intended for administration at or near (within two hours of) bedtime. The present nutraceutical should be taken at least two hours after food, milk, milk products or calcium supplements, preferably at bedtime, and is intended for long-term use. Patients should also receive calcium or vitamin D supplements if they are not getting enough from their diet, after taking into consideration any vitamin D administered with the present supplement. A typical oral dosage form could contain 450 mg strontium (citrate), 2000 IU vitamin D3, 60 mcg Vitamin K2, and 5 mg of melatonin, together with customary pharmaceutically acceptable excipients and diluents, in a form typically intended for oral administration such as a tablet(s), a capsule(s), caplet(s), caplique(s), lozenge(s), sachet(s), stick pack(s), fast-dissolve wafer(s) or strip(s), or piece(s) of chewing gum, without limitation. The oral dosage form may also be in a liquid solution, containing one or more of the above-described active agents or other similar active agents described below; if the active agents are in separate solutions the combination therapy may be implemented by administering one or more solutions to the patient at the same time. The active agents may also be administered individually or in any combination and delivery method in the nighttime time frame described herein. The combined active agents, including suitable combinations, may also be used as constituents or additives in food supplements including but not limited to nutrition bars, nutrition wafers, nutrition powders, nutritional beverage mixes and prepared drinkstypically containing but not limited to one or more of the following ingredients in any combination: protein, carbohydrate, fats and oils, fatty acids, vitamins and minerals, fiber, prebiotics, probiotics, herbals, plant extracts, amino acids, antioxidants, polyphenols, alkaloids, sweeteners, or other nutraceutical constituents. Optimally, when the combined active ingredients include additional nutritional componentssuch as protein, carbohydrate, etc.ideally the traditional nutritional constituents are taken at least 3-hours prior to the bedtime dose of the invention to minimize nighttime digestion and a subsequent rise in the postprandial glucose and insulin responses affecting glucose tolerance. Taking the combined active ingredients, if also containing calcium from dairy or other source of calcium, should also be at least 3-hours prior to the bedtime dose containing melatonin plus the additional active(s), to encourage strontium absorption and bioavailability. Although most usually the combined active agents are given with minimized if any additional calories due to the optimal late day (within two hours of bedtime) administration of at least the melatonin component, it is also general wisdom that not eating late at night and ceasing daily caloric intake well before bedtime is beneficial to overall health promotion and weight control.

[0013] Furthermore, the medically optimal way to administer the combinational therapy is to administer strontium, vitamin D, vitamin K and melatonin orally in a single or multiple capsules, tablets, dissolvable beverage powder preparations, such as powder in packets, or as a single dose liquid-type shot, even though other routes of administration are acceptable. Delivery methods may also include specific preparationsinvolving the active ingredients, excipients, or encapsulation, tableting or other routes-of-delivery materialsto include nano and micro particle, micro-encapsulation, liposomes, phytosomes, emulsions, oil-surfactants, fatty acid, colloidal dispersions, cyclodextrins, polyethylene glycol, controlled release, sustain-release, delayed-release, timed-release, bi-phasic release, gastro-retentive, gastric acid-resistant, enzyme coupling, compounded, prebiotic and probiotic combinations, amino acid, and any other manufacturing method that is intended to enhance absorption, bioavailabilty, digestive comfort, gut receptors and microbiome diversity, and therapeutic effectiveness, including desirable off-target and any additional therapeutic or quality-of-life (QOL) enhancing applications.

[0014] A good kit type formulation for the present invention is in combination with a daytime calcium supplement, vitamin D supplement, or any other vitamin, mineral and nutraceutical combination, in any dosage and combination, with the present formulation or co-administration at night (that is within two hours of bedtime), to include any additional vitamin, mineral (except calcium), nutraceutical, or combinations thereof. The inventors envision a dynamic and continual 24/7 therapy period with this combination that slows bone loss during the day and stimulates new bone formation at night.

[0015] Assertions made in this specification are corroborated in published data (Maria, S., Swanson, M. H., Enderby, L. T., D'Amico, F., Enderby, B., Samsonraj, R. M., Dudakovic, A., van Wijnen, A. J., Witt-Enderby, P. A., Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures, Aging, 9 (1): 256-285, 2017), collected during a formal clinical study. Comprehensive treatment of the study results will therefore be available from public sources when examination of this patent specification begins and/or can be considered in corroborated form. Having said that, however, key conclusions from both the clinical trial and the MenQOL (Menopause-Specific Quality of Life questionnaire) sexual domain scores are summarized as follows. The combination therapy discussed above significantly increased lumbar spine bone mineral density (BMD) by 4.3% and left femoral neck BMD by 2.2%, with a possible trend towards increase in hip BMD from baseline after one year in post-menopausal osteopenic women. This is comparable to bisphosphonates. As a consequence, the 10-year vertebral fracture risk probability was decreased by 6.48%, as compared to 10.8% increase in placebo. The inventive therapy significantly increased bone formation marker P1NP, while not increasing bone resorption marker Ctx. This was shown to be due to an increase in osteoblast formation, a decrease in osteoclast formation and a decrease in osteoblastic metabolic markers (i.e., PPAR gamma and GLUT4) known to be involved in diabetes and targets of diabetic pharmacotherapies. The present inventive therapy also showed positive effects on inflammatory status, height, weight, and lean body mass and also lessened the sexual symptoms of menopause, increased sexual libido and desire, and showed improvements with respect to sleep quality, gastrointestinal upset and general aches and pains. In addition, the present formulation or co-administration surprisingly shifted human mesenchymal cells from adipogenesis to osteoblastogenesis (fat to bone). With respect to restoration of sexual function and interest, we relied on the results of the MenQOL-Intervention survey conducted with members of the clinical trial. MenQOL vasomotor, physical, and psychosocial domain scores did not change significantly with the present treatment. However, after twelve months of treatment with the present invention, improvements in sexual domain scores occurred opposite to what was observed for placebowhich was completely unexpected because no change in the MenQOL scores for sexual domain changed, in a related prior study. The prior study was a clinical trial investigation of melatonin alone, in which administration of 3 mg melatonin for six months did show an improvement in MenQOL scores as to physical domain but no improvement as to sexual domain. The improvement in sexual domain occurred concurrently, in the clinical trial population of the present invention, to the measurable improvement in bone density attributable to the co-administration of the herein disclosed constituents, with melatonin per se as a constant of the present invention.