WO2002034069A2

WO2002034069A2 - Supplement and method for nutritional supplementation of calcium, including a prophylactic motility agent

Info

Publication number: WO2002034069A2
Application number: PCT/US2001/051238
Authority: WO
Inventors: David S. Chance; Dilip Shah; James W. Warren
Original assignee: Banner Pharmacaps, Inc.
Priority date: 2000-10-26
Filing date: 2001-10-25
Publication date: 2002-05-02
Also published as: WO2002034069A3; AU2002234178A1

Abstract

The present invention combines a supplementary effective amount of calcium compound, such as calcium carbonate, in the same dosage form with a prophylactic motility agent, such as docusate sodium.

Description

NUTRITIONAL SUPPLEMENT AND METHOD OF USE Field of the Invention

The present invention relates generally to nutritional supplements and more particularly to calcium supplements with a docusate additive. Background of the Invention

Bone health is an important aspect of well being, regardless of age, sex, or race. Increased calcium intake may alleviate a variety of ailments associated with poor bone health. For example, Osteoporosis is a medical condition that results in the loss of bone structure and strength. Increased calcium intake is believed to alleviate the harmful effects of Osteoporosis.

With age, the rate of bone resorption exceeds that of bone formation and the condition known as Osteoporosis results. Osteoporosis currently afflicts more than 25 million Americans putting them at increased risk of broken hips, wrists, and collapsed vertebrae. In the United States alone, about 1.5 million broken bones each year are attributed to Osteoporosis and the medical cost of treatment is in excess of $10 billion. About half of these fractures are to back ^• vertebrae, which can cause a great amount of pain as well as permanent deformity. There are also more than 200,000 hip fractures annually in the United States. These fractures are often debilitating and can lead to long-term nursing home care.

The loss of bone mass appears to be partly a natural part of the aging process itself. Thus, Osteoporosis is a disease that health professionals will encounter more in the decades ahead because the average age of the population will continue to rise. Osteoporosis weakens bones to the point where relatively little trauma can cause a fracture. Increased calcium intake may alleviate the harmful effects of Osteoporosis, and other bone health ailments. People who cannot or do not wish to consume milk regularly may find it difficult to meet the recommended daily calcium intake of about 1200 to 1300 mg for some age groups. Calcium supplementation offers a solution to meet the recommended daily consumption. Negative side effects, however, such as constipation, bloating, and gas are sometimes reported with the use of calcium supplements. Consequently, the compromise of intestinal motility can lead to decreased compliance with a calcium supplementation program.

As described in more detail below, the effective amount of calcium one takes as a supplement depends on his/her age, dietary intake of calcium from other sources, and a variety of other factors. The amount is also dependent on the amount of other substances in the diet that influence calcium absorption and/or excretion. Certain studies have shown that a calcium intake of up to 2000 mg daily appears to be safe for most people. See, NIH Consensus Development Panel on Optimal Calcium Intake, JAMA, 272:1942-8 (1994), herein incorporated by reference in its entirety. However, even 1000 mg of daily calcium supplementation may increase constipation in some people.

A suggested solution to the intestinal problems associated with calcium supplementation is to provide a separate laxative supplement in addition to the calcium compound. This solution, however, is not ideal. The problems associated with any supplementation, such as swallowing, remembering to dose, remembering how often to dose, and other compliance problems are doubled by the addition of a laxative supplement. Additionally, for example, the person taking the supplement often experiences intestinal discomfort prior to understanding that the calcium supplement is the cause of the problem. Thus, the separate laxative supplement often is taken as an afterthought to relieve any associated intestinal discomfort. There is a need, therefore, to prophylactically alleviate intestinal discomfort and constipation associated with calcium supplementation in a single dosage form.

Summary of the Invention

The present invention overcomes the deficiencies of the prior art by combining a supplementary effective amount of calcium compound, such as calcium carbonate, in the same dosage form with a prophylactic motility agent, such as docusate sodium. In this manner, the motility agent, present in an amount sufficient to counteract the constipatory effects of the calcium compound, prophylactically enhances intestinal motility and warrants a higher compliance with a calcium supplementation program. These and other aspects of the present invention as disclosed herein will become apparent to those skilled in the art after a reading of the following description of the preferred embodiments.

Detailed Description of the Preferred Embodiment The present invention is a nutritional supplement that includes an effective amount of calcium compound for dietary supplementation combined in the same dosage form with a motility agent in an amount sufficient to counteract the constipatory effects of the calcium compound.

In one embodiment, the motility agent is docusate or a docusate salt, such as docusate calcium, docusate potassium, or docusate sodium. Docusate salts are chemically referred to as l ,4-bis(2-ethylhexyl) sulfosuccinates, dioctyl sulfosucciantes, or butanedioic acid, sulfo-1,4- bis(2-ehtylhexyl) ester salts. Docusates are fecal softeners used in the management of constipation. Docusates are anionic surfactants that are considered to act primarily by increasing the penetration of fluid into the feces. One monograph suggests a usual daily dose by mouth up to 300 mg given in divided doses. Docusate sodium has been given in doses of up to 500 mg daily. While the laxative effects of docusates are known, docusates have not been heretofore recognized as a prophylactic agent for use in counteracting the constipatory effects of calcium supplementation. As described in more detail below, the present invention provides a prophylactic constituent to avoid constipation that may be related to the calcium supplement, the age of the average consumer of calcium supplementation, or a combination of both factors.

The amount of motility agent, such as a docusate salt, sufficient to counteract the constipatory effects of the calcium supplement will vary depending upon the amount of the calcium in the supplement, the age and weight of the user, the diet of the user, and a variety of other factors. The amount of the prophylactic motility agent should be that amount that effectively manages the intestinal motility of a user.

As used herein the phrase "intestinal motility" should be interpreted to include, among other things, the state of gastrointestinal regulation wherein bowel movements occur with normal or healthy frequency. While the present invention is described in conjunction with a docusate motility agent, any other appropriate prophylactic motility agent or combinations may be used. For example, senna, from Cassia acutifolia Delile or Cassia angustifolia Vahl, is an herbal having laxative effects. Senna may be used within the compositions of the present invention so as to provide an herbal motility agent. Preferably, the calcium compound used in the present invention is calcium carbonate. As will be recognized by those skilled in the art, however, other appropriate foπns of elemental calcium may be used. For example, older people who have achlorhydria (about 15-20% of those over the age of 60) may respond better to a calcium citrate supplement because calcium citrate is less dependent on stomach acid as compared to calcium carbonate for absorption. Calcium carbonate is preferred, however, because of its high ratio of calcium anions.

Calcium supplementation is suggested by those skilled in the art for the treatment of a variety of conditions, including, without limitation, osteoporosis, other bone diseases, oral bone loss, certain cancers, hypertension, and preeclampsia. The present invention, thus, should not be limited to use of calcium supplementation for the treatment of Osteoporosis. As used herein, the term "treatment" includes the prevention, lowering, stopping, or reversing the progression or severity of a condition or symptom being treated. As such, the present invention includes both medical therapeutic and/or prophylactic calcium administration, as appropriate. As used herein, the phrase "effective amount," as used in relation to calcium supplementation, is an amount of elemental calcium that is effective in treating the targeted condition or symptom. As one example of an "effective amount" of calcium intake, the NIH Consensus Development Panel on Optimal Calcium Intake, JAMA, 272:1942-8 (1994), earlier incorporated by reference in its entirety, refers to the level of consumption that is necessary for an individual to (a) maximize peak adult bone mass, (b) maintain adult bone mass, and (c) minimize bone loss in later years. As noted above, the level of calcium considered effective, however, varies among individuals based upon age, sex, ethnicity, weight, diet, and activity.

Preferably, the supplement of the present invention delivers approximately 300 mg of elemental calcium, described in further detail below in Formulas 1 and 3. While this amount is below most recommended daily intake values, the 300 mg amount is preferred due to the resulting reduced size of the dosage form and concomitant ease in swallowing. Multiple doses may be had depending upon an individual's recommended daily intake, however, the calcium level is considered "effective" as that term is used herein. As noted above, the recommended daily intake value varies largely and depends upon age, sex, ethnicity, weight, diet, and activity. The 300 mg dosage form is preferred because many older persons suffer from some degree of dyspahgia and, thus, have trouble swallowing large dosage forms. Further, the smaller dosage is believed to provide enhanced absorption of the elemental calcium and, thus, provide improved calcium bioavailability.

The present invention, however, should not be limited to any dosage size. For example, a dosage delivering 600 mg of elemental calcium may be made in accordance with the present invention as shown below in Formulas 2 and 5. The present invention, thus, is applicable to varying dosage sizes. The present invention includes a variety of dosage forms, as well. In this regard, the preferred dosage form for the present invention is a softgel dosage form. Other forms, such as tablets, pills, capsules, troches, or liquid dosages may also be used. As used herein, the term "softgel" is the accepted nomenclature adopted by the SoftGel Association for a soft gelatin capsule. Formerly, the accepted nomenclature was a soft elastic gelatin (SEG) capsule. Generally, a softgel is a one-piece, sealed, soft gelatin shell that contains a fill that is a solution, a suspension, or a semi-solid paste. The present invention, however, is equally applicable to similar dosage forms, such as liquid-fill telescoping two-piece hard capsules. Thus, the phrase "dosage form" should be interpreted to encompass any form suitable for the present invention.

The softgels may be produced in any acceptable manner such as by a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced ribbons of gelatin in a semi-molten state. These ribbons are fed around rollers and brought together at a convergent angle into the nip of a pair of roller dies that include opposed die cavities. Λ fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons, and the resulting soft capsules are dried. Various sheath formulations known in the prior art may be used to encapsulate the fill formulations of the present invention. For example, suitable sheath formulations may include from about 30 to about 50 % by weight gelatin; at least 15% by weight, and preferably up to about 35 % by weight, of a plasticizer; and from about 25 to about 45 % by weight water. Any appropriate gelatin or combination of gelatin may be used. Further, the sheath formulations may also contain other ingredients, such as taste modifiers, opacifying and coloring agents, and moisture retaining agents.

The softgel fill should include an appropriate vehicle for delivery of the combined calcium and docusate compounds. As shown in Table 1 below, one embodiment of the present invention provides an oil-based vehicle. Such a product may be preferred due to its composition base of natural ingredients.

As used herein, the term "oil" may be any vegetable or plant oil such as corn, safflower, peanut, or soybean oil, or a mixture thereof. The wax may be beeswax or any other appropriate wax, including hydrogenated vegetable oil or wax-like substances such as mixed glycerides, or a combination thereof

As used herein, the term "lecithin" should be interpreted to include all forms of lecithin and its active constituents. For example, and not meant to limit the invention, natural lecithin, refined/purified lecithin, modified lecithin, synthetic lecithin, or combinations thereof may be used. Although the present invention is described in conjunction with lecithin and lecithin is the preferred emulsifying agent for reasons of cost and effectiveness, other emulsifying agents, wetting agents, or surface-active agents that impart the advantages of increased metabolism of lipophilic compounds while maintaining the desired physical properties such as flowability, viscosity, plasticity, and consistency may be used.

As shown in Table 1, for an oil-based vehicle the calcium compound should constitute about 71% to about 72% by weight of the fill, the solubilized docusate (e.g. docusate solubilized in corn oil) should constitute about 5% to about 6% by weight of the fill, the oil should constitute about 20% to about 22% by weight of the fill, the wax should constitute about 0.9% to about 2% by weight of the fill, and the lecithin should constitute about 0.4% to about 0.5% by weight of the fill. Preferably, the weight ratio of calcium compound to the remaining ingredients in the fill is from about 2.4:1 to about 2.6:1.

TABLE !

As shown in Table 2 below, another embodiment of the present invention provides a polyethylene glycol ("PEG")-based vehicle.

A preferred PEG-based fill includes PEGs of different molecular weights, preferably PEG 400 and PEG 3350; propylene glycol; and a polyoxyethylene sorbitan monooleate. These ingredients, however, may be substituted or combined with other appropriate excipients to provide a fill material that is homogenous and that is of an appropriate viscosity, as determinable by those skilled in the art, for the encapsulation process. Other combinations may include polyethylene glycols of varying molecular weights, without the addition of a co-solvent such as propylene glycol. Also, other types of alcohols or polyols such as glycerol, propylene carbonate, or glycol ethers may be used as co-solvents rather than propylene glycol, or to replace the liquid polyethylene glycol. As shown in Table 2 below, for a PEG-based vehicle the nutritional supplement of the present invention preferably includes calcium carbonate in an about 64% to about 69% by weight of the fill, solubilized docusate sodium (e.g. solubilized in PEG 50%) in an about 2% to about 11% by weight of the fill, PEG 400 in an amount of about 19% to about 26% by weight of the fill, PEG 3350 in an amount of about 0.2% to about 0.3% by weight of the fill, propylene glycol in an amount from about 1% to about 2% by weight of the fill; and polyoxyethylene sorbitan monooleate in an amount of about 2% to about 5% by weight of the fill. Preferably, the weight ratio of calcium compound to the remaining ingredients in the fill is from about 1.5: 1 to 2:1.

TABLE 2

Other constituents may be added to the fill matrix such as colorants, opacifying agents, flavorants and taste modifiers. The present invention includes a method for providing dietary supplementation of calcium by providing an effective amount of calcium compound for dietary supplementation to an individual in need thereof in conjunction with an effective prophylactic amount of a motility agent to counteract the constipatory effects of the calcium compound. Although specific embodiments of the present invention have been illustrated and described in detail, it is to be expressly understood that the invention is not limited thereto. The above detailed description of the embodiment is provided for example only and should not be constnied as constituting any limitation of the invention. Thus, modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.

Claims

What is claimed is:

1. A nutritional supplement comprising: an effective amount of calcium compound for dietary supplementation; and a prophylactic motility agent in an amount sufficient to counteract the constipatory effects of the calcium compound.

2. The nutritional supplement of claim 1 wherein the motility agent is docusate.

3. The nutritional supplement of claim 1 wherein the motility agent is Senna.

4. The nutritional supplement of claim 1 wherein the calcium and motility agent are suspended in an oil and wax matrix and encapsulated in a softgel.

5. The nutritional supplement of claim 4 wherein the oil and wax matrix comprises: oil; lecithin; and wax.

6. The nutritional supplement of claim 1 wherein the calcium and motility agent are suspended in a PEG-based matrix and encapsulated in a softgel.

7. The nutritional supplement of claim 6 wherein the PEG-based matrix comprises: PEG; propylene glycol; and polyoxyethylene sorbitan monooleate.

8. The nutritional supplement of claim 1 wherein the calcium compound is calcium carbonate.

9. The nutritional supplement of claim 1 wherein the calcium compound and motility agent comprise a softgel fill and wherein the calcium compound is present in an amount of about 60%> to about 75% by weight of the fill.

10. The nutritional supplement of claim 1 wherein the calcium compound and motility agent comprise a softgel fill and wherein the motility agent is present in an amount of between about 2% to 1 1% by weight of the fill.

11. A method for dietary supplementation of calcium comprising: providing an effective amount of calcium compound for dietary supplementation; providing an effective amount of a motility agent to counteract the constipatory effects of the calcium compound.

12. The method of claim 1 1 wherein the calcium compound is calcium carbonate.

13. The method of claim 1 1 wherein the motility agent is docusate.

14. The method of claim 11 wherein the motility agent is Senna.

15. The method of claim 11 wherein the calcium compound and the motility agent are provided as a softgel fill.

16. The method of claim 15 wherein the softgel fill further comprises: oil; lecithin; and wax.

17. The method of claim 15 wherein the softgel fill further comprises: polyethylene glycol; polyoxyethylene sorbitan monooleate; and propylene glycol.

18. A nutritional supplement comprising: an effective amount of calcium compound for dietary supplementation; and a docusate in an amount sufficient to counteract the constipatory effects of the calcium compound.

19. The nutritional supplement of claim 18 wherein the docusate is selected from the group consisting of docusate calcium, docusate potassium, and docusate sodium.

20. The nutritional supplement of claim 18 wherein the calcium compound is calcium carbonate.

21. The nutritional supplement of claim 18 wherein the nutritional supplement is a softgel fill that further comprises a vehicle for delivery of the calcium and docusate.

22. The nutritional supplement of claim 21 wherein the vehicle comprises: oil; wax; and lecithin.

23. The nutritional supplement of claim 22 wherein the calcium compound is calcium carbonate and comprises about 71% to about 72% by weight of the fill; the docusate is docusate calcium in com oil and comprises about 5%. to about 6% by weight of the fill; the oil is vegetable oil and comprises about 20% to about 22% by weight of the fill; the wax is yellow beeswax and comprises about 0.9% to about 2% by weight of the fill; and the lecithin comprises about 0.4% to about 0.5% by weight of the fill.

24. The nutritional supplement of claim 22 wherein the ratio of calcium compound to the remaining ingredients in the fill is from about 2.4:1 to 2.6:1.

25. The nutritional supplement of claim 21 wherein the vehicle comprises: polyethylene glycol; propylene glycol; and polyoxyethylene sorbitan monooleate.

26. The nutritional supplement of claim 25 wherein the calcium compound is calcium carbonate and comprises about 64% to about 69% by weight of the fill; the docusate is docusate sodium in PEG 50% and comprises about 2% to about 1 1% by weight of the fill; the polyethylene glycol is comprised of: PEG 400 in an amount of about 19% to about 26% by weight of the fill; and

PEG 3350 in an amount of about 0.2% to about 0.3% by weight of the fill; the propylene glycol comprises about 1%> to about 2% by weight of the fill; and the polyoxyethylene sorbitan monooleate comprises about 2% to about 5% by weight of the fill.

27. The nutritional supplement of claim 25 wherein the ratio of calcium compound to the remaining ingredients in the fill is from about 1.5:1 to 2: 1.

28. A nutritional supplement comprising: an effective amount of calcium compound for dietary supplementation; and Senna in an amount sufficient to counteract the constipatory effects of the calcium compound.

29. The nutritional supplement of claim 28 wherein the calcium compound is calcium carbonate.

30. A softgel nutritional supplement comprising: a fill comprising: calcium compound in an amount of about 64% to about 72% by weight of the fill; and a solubilized docusate selected from the group consisting of solubilized docusate calcium, solubilized docusate potassium, and solubilized docusate sodium, being present in an amount of about 2% to about 11% by weight of the fill, wherein the ratio of calcium compound to the remaining ingredients in the fill is from about 1.5:1 to about 2.6: 1.