Gamma-polyglutamic acid and zinc compositions

Abstract

To provide compositions for administering zinc, including nutritional supplement compositions, comprising γ-polyglutamic acid, a zine salt, and a gastro-resistant material for use as a dietary supplement to provide zinc to persons desiring or in need thereof.SOLUTION: A composition formulated as a solid dosage form for oral administration of zinc, for use as a pharmaceutical for the treatment of zinc deficiency or zinc inadequacy, comprises: 10 wt.% to 40 wt.% of γ-polyglutamic acid having a number average molecular weight in the range from 5 kDa to 300 kDa; a zinc salt such that the amount of zinc present per solid dosage form is 1 mg to 100 mg; and a gastric-resistant material.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of nutritional supplements, and more particularly to those with zinc deficiency or zinc insufficiency. solid or artificial food for providing zinc to any person, including humans, who desires or needs it; The present invention relates to a liquid oral dosage form containing gamma-polyglutamic acid and a zinc salt for use as a supplement. The present invention relates to a composition comprising: [Background technology]

[0002] Zinc is an essential mineral for microorganisms, plants and animals, including humans. Nearly 100 metalloenzymes are required for numerous catalytic, structural, and regulatory functions in the cell. These metalloenzymes require zinc for their function, and these metalloenzymes are distributed among all six enzyme classes. Zinc also binds to proteins and affects their structure. Proteins fold into specific structures as a result of zinc coordination to specific amino acids. , and the folded protein is biologically active. Coordination affects the catalytic activity of another metal in a metalloenzyme by altering the structure of the enzyme. Zinc has also been identified as a regulator of gene expression, e.g., metal response element transcription. It acts by binding to the factor.

[0003] There is no mechanism for storing zinc, so regular intake of zinc is not sufficient to maintain the mineral in the body. Zinc is generally obtained through the diet. Food sources of niacin include red meat, poultry, seafood such as crab and lobster, beans, nuts and and dairy products. However, it is also present in foods such as wholemeal bread, cereals and legumes. Phytates present in the body (e.g., myo-inositol hexaphosphate) bind to zinc and This reduces zinc absorption in the gastrointestinal tract. Dietary imbalances can lead to inadequate zinc levels. Diets particularly rich in phytates have been linked to zinc deficiency in some populations. Deficiency can occur in conditions such as sprue, Crohn's disease, short bowel syndrome, or zinc carrier It can also occur in individuals with impaired zinc absorption due to a genetic defect in the protein.

[0004] It is estimated that 25% of the world's population is at risk of zinc deficiency. Maret W, Sands tead HH, “Zinc requirements and the risks and benefits of zinc supplementation, ” J. Trace Elem. Med. Biol. 20 (1): 3-18 (2006). Zinc deficiency or insufficiency can affect immune function. disability, loss of appetite, delayed wound healing, growth retardation, impotence, delayed puberty, taste disorders, has been linked to behavioral and other illnesses.

[0005] To minimize the chance of inadequate or deficient zinc levels, some foods, e.g. Cereals are fortified with zinc, which produces crops with increased zinc content. Nutrient (dietary) supplements are also available. Such supplements contain zinc in the form of, for example, zinc sulfate, zinc acetate, or chelated zinc. However, there are currently no zinc supplements on the market that contain zinc oxide. These agents have the disadvantage that they introduce zinc salts directly into the stomach. Lead salts are known to cause stomach irritation or even stomach bleeding. Zn 2+ The ion is highly soluble in the gastrointestinal tract, along with other divalent metal ions, such as calcium, magnesium, copper, and iron. High zinc intakes, such as can occur with supplements, can affect copper absorption. It has been reported that copper can inhibit growth and lead to copper deficiency or anemia. aghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, et al. copper deficiency: a report of three cases initially recognized on bone marrow e xamination,” Am. J. Clin. Pathol. 123:125-31 (2005). It is absorbed from a diet containing zinc-binding foods or through natural absorption mechanisms. Supplementation with other nutrients that compete with or bind to zinc, such as copper, iron, or phosphorus It must be taken more than 2 hours apart from the medication.

[0006] Thus, a zinc supplement composition that avoids the problems associated with currently available compositions, particularly gastric Avoids upset and gastric irritation and does not compete with divalent metal ions for bioabsorption in the gastrointestinal tract There remains a need for compositions that avoid this. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Maret W, Sandstead HH, “Zinc requirements and the risks and benefits of zinc supplementation,” J. Trace Elem. Med. Biol. 20 (1): 3-18 (2006) [Non-patent document 2] Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, et al. “Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination,” Am. J. Clin. Pathol. 123:125-31 (2005) Summary of the Invention

[0008] Zinc to those in need that overcomes the problems and side effects recognized in the art The present invention provides a nutritional supplement composition for providing gamma-polyglutamic acid. (γ-PGA), zinc salts and gastro-resistant materials The present invention is directed to compositions for administering zinc formulated as a solid or liquid dosage form.

[0009] Without being limited by theory, the present invention relates to the administration of hydroxybenzoates (HBD) within the dosage form until the dosage form has passed through the stomach and entered the intestine. It is intended to provide a solid or liquid dosage form with gastro-resistant material to prevent the contents from being expelled. In the intestine, the present invention provides zinc that associates with γ-PGA in the large intestine and is transported therewith. It can be absorbed by being absorbed in the small intestine, and does not necessarily involve divalent metal ions acting in the small intestine. The intention is to provide zinc salts in the presence of γ-PGA so as not to rely on transport mechanisms related to do.

[0010] In one embodiment, the composition has an average molecular weight ranging from about 1 kDa to about 1000 kDa. The formulation includes gamma-PGA, zinc salts and gastro-resistant materials. In one embodiment, the composition comprises γ-PGA and zinc in a solid or liquid dosage form. and a means for delivering said γ-PGA and said zinc salt to the intestine. The corresponding structure or material for performing the function of delivering the components of the composition to the intestine is a gastroresistant material. as part of a solid dosage form or as a suspended solid in a liquid dosage form, e.g., granules, particles etc. are provided as part of the

[0011] In combination with any of the above embodiments relating to solid dosage forms, the composition may be in a solid dosage form, e.g. For example, capsules or tablets may be prepared with fillers and / or binders and / or granules. one or more excipients selected from a compressing agent and / or a compression aid and / or a disintegrant and may further comprise a lubricant and / or a glidant.

[0012] The present invention relates to a method for preparing a solid dosage form of the nutritional supplement composition disclosed herein. In one embodiment, the solid dosage form is a tablet. The dosage form is a capsule.

[0013] In one embodiment, the method comprises mixing γ-PGA and a zinc salt and one or more excipients. The mixture is granulated, and a lubricant and optionally additional excipient(s) are added to the granules. The resulting composition is tableted into tablets, and the tablets are coated with a gastro-resistant substance. In one embodiment, the method comprises adding γ-PGA and a zinc salt and one The above excipients are mixed, the mixture is granulated, and optionally additional excipient(s) are added. with the granulated mixture and then encapsulating the resulting composition. Alternatively, the capsule may include or be provided with a gastro-resistant coating.

[0014] In one embodiment, the method comprises the steps of: γ-PGA and a zinc salt; a gastro-resistant binder; and one or more the excipients, and the mixture is granulated, followed by addition of a lubricant and optionally additional excipients (one or more). (or a plurality of) with the granulated mixture, and tableting the resulting composition into tablets, In one embodiment, the method further comprises coating the tablet for appearance, mechanical stability, etc. The method comprises mixing γ-PGA and a zinc salt, a gastro-resistant binder, and one or more excipients, and Granulating the mixture and optionally mixing additional excipient(s) with the granulated mixture. and then encapsulating the resulting composition.

[0015] In one embodiment, the method comprises mixing γ-PGA and a zinc salt and one or more excipients. In some embodiments, the solid mixture composition includes: The product is formulated into a suitable dosage form, such as a tablet or capsule.

[0016] The present invention provides a liquid dosage form of the nutritional supplement composition disclosed herein, prepared as a liquid suspension. It also addresses methods for doing so. In one embodiment, the method comprises the steps of: γ-PGA and a zinc salt; a gastro-resistant binder; and one or more the excipients, granulating the mixture, and then suspending the granulated solid in a suitable liquid. Methods for providing zinc to individuals who desire or need it are also provided. In one embodiment, the method comprises administering to a human desiring or in need of zinc supplementation. The method includes administering a solid or liquid dosage form of the nutritional supplement composition disclosed herein to the patient. In some embodiments, the method includes administering up to 100 mg, up to 75 mg, up to 50 mg, up to 25 mg. or up to 10 mg of zinc is provided in the solid dosage form(s) administered.

[0017] These and other objects and features of the present invention are described in the following detailed description and claims. The range will be clear to those skilled in the art. DETAILED DESCRIPTION OF THE INVENTION

[0018] The components used in the compositions and formulations described herein are suitable for use in nutritional supplement products. and in some cases are of a grade approved by regulatory authorities for use in means a pharmaceutical or medical grade compound or substance.

[0019] The abbreviations used herein have the following meanings: "kDa" means kilodalton; "wt %" means percent by weight; Active ingredient Zinc is available as zinc(II) salt (equivalent to Zn 2+ salt), where the counterion (anion) The anion) can be any suitable inorganic or organic anion. The anions are those that are tolerated by the human body, including non-toxic anions. , formula Zn 2+ X 2- Or Zn 2+ (X - )2 or even Zn 2+ (X - )(Y - ) where X and Y are suitable anions. The anion can be , selected from the group of anions that are components of approved food additives or nutritional supplements In some embodiments, the zinc(II) salt is a nutritionally acceptable zinc salt. , the zinc(II) salts are approved for use in foods or nutritional supplements. The anion is selected from the group of zinc(II) salts. In some embodiments, zinc(II) The salts are pharmaceutically acceptable zinc salts. Examples of zinc salts are zinc chloride, zinc sulfate, zinc citrate, zinc phosphate ... Zinc acid, zinc acetate, zinc picolinate, zinc gluconate, amino acid-zinc chelates, e.g. For example, zinc glycine or other amino acids known and used in the art. Two or more different zinc salts may be present in either the composition or formulation. They can be used together in any proportion to provide

[0020] The amount of zinc contained in a single dosage form is generally about 1 to about 100 mg of zinc (zinc(II) ion). Therefore, the specific zinc salt(s) used in the formulated composition The amount will be higher because the amount of salt must account for the weight of the counterion. Considering only (II), the amount provided in the dosage form may be up to about 100 mg, up to about 75 mg, up to about 50 mg, up to about 25 mg, up to about 10 mg zinc, or up to about 5 mg The amount of zinc(II) provided is generally at least about 1 mg. Commonly available replenishers include, for example, 20, 25, 30, 50, 75 and even 100 ml g of zinc. Any amount of zinc in this range or higher may be provided. It is acceptable as long as the amount taken does not cause excessive levels of zinc absorption. The tolerable upper intake level for zinc in adults is approximately 40 mg / day (for children Although it is less effective in some cases, it is unlikely that all of the zinc in the dosage form will be absorbed; It should be recognized that some of the zinc will pass through the body unabsorbed. The amount of zinc in each formulation is likely to vary depending on the formulation, so the upper limit of the zinc content in each formulation is Ascertain the level of uptake provided by the formulation and adjust the upper limit for the dosage form accordingly. The compounds can be tested by methods known in the art for the prevention of cancer.

[0021] Gamma-polyglutamic acid (or γ-polyglutamic acid or γ-PGA) is a glutamic acid It is a polymer of glutamic acid (an amino acid), where the backbone of the polymer contains amino groups and formed by peptide bonds linking carboxyl groups (at the γ-carbon) in amino acid side chains γ-PGA is formed from the L-isomer, D-isomer, or DL ​​racemate of glutamic acid. Any of these forms can be used, and two or more types can be used. The different forms can be used together in any proportion. The body forms can be synthetic or derived from natural sources. , for example, in Japanese natto and kelp. Organisms usually produce poly(alanine) only from the L isomer. The specific bacterial enzyme that produces γ-PGA is either one of the isomers or Polymers can be made from either or both isomers.

[0022] γ-PGA of various sizes and various polymer dispersities can be used. The polymer molecular weight of γ-PGA is generally at least about 1 kDa and at most about 1000 kDa. In some embodiments, the polymer molecular weight of the γ-PGA is at least about 1 kDa. or at least about 5 kDa, or at least about 10 kDa, or at least about 20 kDa, or at least about 30 kDa, or at least about 35 kDa, or less In some embodiments, γ-PG is about 40 kDa, or at least about 50 kDa. The polymer molecular weight of A is at most about 700 kDa, or at most about 500 kDa, or at most about 100 kDa. Large, about 300 kDa, or up to about 200 kDa, or up to about 100 kDa The acceptable polymer molecular weight range can be selected from any of the polymer molecular weight values ​​shown above. In one embodiment, the polymer molecular weight is about 5 kDa to about 500 kDa. In another embodiment, the polymer molecular weight ranges from about 5 kDa to about 300 kDa. In one embodiment, the polymer molecular weight is in the range of about 50 kDa to about 100 kDa. In one embodiment, the polymer molecular weight is about 100 kDa (kDA). In this case, the polymer molecular weight is about 50 kDa (kDA).

[0023] Polymer molecular weights are typically measured, for example, by gel permeation chromatography (GPC). The number average molecular weight (M n ) The polymer mass is given by M n as Other measurement techniques are also mentioned, such as mass (weight) average molecular weight (M w ) used to determine The specifications for any given polymer can be expressed in various polymer mass expressions. can be converted between

[0024] The amount of γ-PGA contained in a solid dosage form is generally in the range of about 10% by weight to about 40% by weight. In some embodiments, the amount is about 20% by weight or about 30% by weight. is generally determined by the desired molar ratio between zinc and polyglutamic acid monomer units, the mass of zinc salt ( (accounting for the weight of the counterion) as well as that required to provide an acceptable formulated dosage form. For example, the greater the amount of γ-PGA and zinc salt used, the greater the For example, the amount of excipient that can be added for a given dosage form overall size is small. The author has considered the trade-off between the amount of active ingredient and the amount and type of excipients required to obtain a stable dosage form. The desired ratio between zinc and γ-PGA can be easily achieved by adjusting the dosage form. It can also be expressed as the ratio of milligrams of zinc to the weight percent of γ-PGA. The ratios are 5mg:10% by weight; 5mg:20% by weight; 5mg:40% by weight; 30mg: 10% by weight; 30mg:20% by weight; 30mg:40% by weight; or even 100mg g: 10% by weight; 100mg: 20% by weight; 100mg: 40% by weight; or a combination of these Any other set of values ​​within the range indicated by the typical ratio or otherwise described herein. This includes a set of values ​​that are apparent from the values ​​quoted for each component.

[0025] The amount of γ-PGA contained in the liquid dosage form is generally in the range of about 0.01% by weight to about 10% by weight. In some embodiments, the amount is about 0.1% by weight or about 1% by weight. The amount used is generally based on the desired molar ratio between zinc and polyglutamic acid monomer units.

[0026] The gastroresistant material is included as a gastroresistant outer coating or as a gastroresistant binder; It is considered an active ingredient in compositions and formulated dosage forms for the purposes of this disclosure. The materials that make up the external coating or binder prevent the release of zinc salt and γ-PGA from the dosage form. The function of gastroresistant materials is to delay the release of food from the stomach until it passes through the stomach and into the intestine. , which does not appreciably dissolve or swell in the acidic environment of the stomach (pH about 3), but -Sufficiently soluble in a slightly alkaline environment (pH 7-9) to release its contents or a matrix or polymer or other barrier that will swell. Ingredients and enteric binders are examples of gastroresistant materials.

[0027] Examples of gastroresistant materials are cellulose acetate phthalate, cellulose acetate succinate, trimellitate acetate, cellulose phosphate, hydroxypropyl methylcellulose phthalate, Copolymers of two or more monomers: (i) acrylic acid esters, (ii) methyl acrylate esters, and (iii) methacrylic acid, polyvinyl acetate phthalate, acetic acid Hypromellose succinate, hypromellose phthalate, sodium alginate, shellac and zain.

[0028] Numerous grades and pharmacopeia standards exist for gastro-resistant materials, including: To select an appropriate material to provide the function of delivering zinc and γ-PGA to the intestine Provides useful guidance. Coating thickness and polymers in the outer coating By controlling the composition or amount of binder and polymer composition, the release point can be made earlier. or slower, or may be regulated to occur within specific general regions of the intestine. Examples of the degree of control that can be achieved are C Acrycoat® from Orel Pharma Chem (India) A line of methacrylic acid copolymers available under USP / NF methacrylate copolymers, e.g., Acrylic acid copolymer, Type A-NF (used at 4-5%, typically in the dosage form contents) to the jejunum); USP / NF methacrylic acid copolymer, Type C-NF (4-5% and USP / NF Metabolites, which typically deliver the contents of the dosage form to the duodenum; and Acrylic acid copolymer, Type B-NF (used at 10-20%, typically in the dosage form) The latter (Type B-NF) can be found in Delivery has been achieved with pH-dependent polymers, but pH-independent polymers have also been shown to be effective in the colon or It can be used for intestinal delivery.

[0029] compound The zinc salt and γ-PGA active ingredients are administered in oral solid dosage forms, such as tablets, capsules or oral Related forms for administration, such as minitablets, caplets, etc. The dosage form may include a gastro-resistant binder or may further comprise a gastro-resistant binder. It can be formulated to have a durable outer coating.

[0030] The zinc salt and γ-PGA active ingredients are formulated into an oral liquid dosage form, e.g., a liquid suspension. The formulation components and methods for preparing embodiments of the liquid dosage form are further described below. will be done.

[0031] The zinc salt and gamma-PGA active ingredients are suitable for use in supplement products and are Combined with suitable excipients to produce a dosage form, such as a tablet or capsule. Typical excipients include fillers, binders, disintegrants, glidants, lubricants as well as buffers, preservatives, These include antioxidants, flavoring agents, sweeteners, coloring agents, etc. The amount and type of excipients to be added are , for various purposes, such as improved dosage form integrity, improved bioavailability, stability, manufacturing, They can be selected for coating, appearance and / or compliance. Some excipients may serve more than one purpose and / or have more than one effect. The above features can be provided.

[0032] The bulking agents can be water soluble or water insoluble, with one or more of each type being Examples of water-soluble bulking agents include, but are not limited to, those known in the art. As mentioned above, sugars such as glucose, fructose, sucrose, mannose, dextrose, trose, galactose, etc., and sugar alcohols such as mannitol and sorbitol Examples of water insoluble bulking agents include, but are not limited to, those known in the art. Contains wax, long chain fatty acids, talc, kaolin, silicon dioxide, titanium dioxide, aluminum These include cellulose, starch, powdered cellulose, microcrystalline cellulose, etc.

[0033] Binders include, but are not limited to, cellulose derivatives, such as cellulose acetate, as known in the art. Carboxymethylcellulose calcium, carboxymethylcellulose sodium, acetate Cellulose talc, ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl Methylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone and starches , modified starches, such as partially hydrolyzed starches, e.g., maltodextrin , sugars, gelatin, natural or synthetic gums, etc.

[0034] As noted above, in some embodiments, the gastro-resistant binder is a zinc(II) salt and γ-PGA. It may be included in the formulation as a binder which functions to delay release until the intestine. When a gastro-resistant binder is used, it may be used in combination with other (non-gastro-resistant) binders. It can be done.

[0035] Disintegrants include, but are not limited to, carmellose, carmellose, as known in the art. Sodium, croscarmellose sodium, crospovidone, alginates, low-substituted Hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch This includes

[0036] Lubricants include, but are not limited to, silicas, silicates, talc, as known in the art. Contains calcium carbonate, calcium phosphate, etc. Lubricants include, but are not limited to, alkali metal or alkali lubricants, as known in the art. Earth metal stearates, oleates, benzoates, acetates, chlorides, etc. include.

[0037] Other types of excipients, such as buffers, preservatives, antioxidants, flavors, sweeteners, colorants, These components are well known and can be readily selected and applied to formulations by those skilled in the art. Cut.

[0038] Other types of active ingredients that are amenable to absorption in the intestine, such as vitamins, minerals, and nutrients Proteins and other nutritional or dietary supplements also fall within the scope of the present invention unless otherwise specified. may be added to the solid or liquid compositions and formulations described herein without can.

[0039] The solid or liquid compositions and formulations described herein may alternatively contain zinc salt(s). and γ-PGA and a gastro-resistant outer coating or gastro-resistant binder, Unless otherwise inconsistent with the Document, The solid or liquid compositions and formulations are present in the compositions of the prior art, or Any component (single component) not otherwise required by the disclosed invention. one or more), e.g., devoid of or substantially free of active ingredients and / or excipients You can also do this without doing anything.

[0040] Methods for preparing solid dosage forms The zinc salts and γ-PGA and selected excipients may be used individually or in combination. To be sized, declumped, or pulverized The various components can be combined by dry mixing or by wet or dry mixing. Granulation may be carried out by conventional granulation, spraying, extrusion, rolling or fluidized bed granulation or other methods known in the art. and then optionally milled. do.

[0041] The method for preparing the solid dosage form comprises mixing the desired amount of zinc salt(s) and γ-PGA and The excipients may be mixed together, which may include one or more bulking agents and / or one or more one or more binders and / or one or more disintegrants and / or one or more lubricants and and / or one or more lubricants. As noted above, in some embodiments, The above binders can be gastro-resistant binders, which can be used in combination with other (non-gastro-resistant) binders. If a granulation step is involved, any of the excipients may be used in combination. It can be added in whole or in part before, during or after the granulation process. In one of these embodiments, some or all of the lubricant is mixed in after the granulation step. In part 1, a lubricant is also mixed in after the granulation step.

[0042] The granulation process may involve the use of a solvent, to wet the blend of components as they are granulated. For example, if it involves the use of water or organic solvents or aqueous organic solutions, the resulting product The solvent is typically dried to remove any residual solvent. Examples of organic solvents are those known in the art. As is known, organic solvents include ethanol and isopropanol, etc. Preferably, Substantially all of the water is removed in the drying process. If it is part of the medium, it preferably accounts for no more than 10% by weight, or no more than 5% by weight. No, or not more than 2% by weight of water is left after drying for the next step.

[0043] Blended or granulated solids may be tableted by compressing, compacting or molding the solids. In some embodiments, the tablets can then be formed into tablets by Generally, the drug is coated with a gastro-resistant coating, such as a gastro-resistant substance and optionally other additives. A vehicle (e.g., plasticizer, emulsifier) ​​is dissolved or dispersed in an aqueous or organic solvent, and then Coating methods known in the art include spray coating, fluidized bed coating, pan coating, etc. In some embodiments, the tablets are applied in any of a number of ways, including visually, mechanically, The coating is used for the purpose of stability, chemical stability, etc., but the coating contains No sexual material is included.

[0044] Alternatively, the blended or granulated solids may be filled into capsules or caplets. The term capsule includes soft capsules, hard capsules, gelatin capsules, and gelatin capsules. Gelcaps, including vegetable capsules, one-piece or two-piece Enteric coated capsules are available (e.g., enteric coated capsules). The capsules are filled, sealed, and then By this method, a solution or dispersion of the substance, optionally together with other excipients, is used to prepare a gastro-resistant coating. In another embodiment, the mixed or granulated solid can be coated with a coating. and gastro-resistant binder material, and such solids are placed in capsules lacking an enteric coating. can be filled.

[0045] The size and shape of both the tablet and capsule are not particularly limited. The desired dose of PGA can be formulated into tablets or capsules that are not excessively large. It is expected that this can be done.

[0046] Exemplary methods for preparing tablet dosage forms according to embodiments of the present invention are described below in Examples 2 and 3. 4 is provided. Methods for preparing liquid dosage forms One method for preparing a liquid dosage form is to combine the desired amounts of zinc salt(s) and γ-PGA and and a gastro-resistant binder mixed with suitable excipients to form a granulated solid or suspension in a solution. This includes preparing other solid forms suitable for

[0047] Suitable excipients include fillers, binders, disintegrants (as described above for solid dosage forms), agents as well as buffers, preservatives, antioxidants, etc. The amount and type of excipients to be added are used for various purposes, such as improved dosage form integrity, improved bioavailability, stability, manufacturing Some excipients may be selected for appearance and / or compliance. can serve more than one purpose and / or offer more than one improved feature. It can be provided.

[0048] The zinc salts and γ-PGA and gastro-resistant binder and selected excipients may be individually or a combination thereof, may be sized, de-lumped, or pulverized. The various components can be mixed by wet or dry granulation, spraying, extrusion, rolling or pouring. It can be granulated by moving bed granulation or other such techniques known in the art; This can then optionally be milled. In particular, the granulation process is described above in relation to solid dosage forms. Therefore, the Zn(II) salt and γ-PGA can be used as described above. Granulated compositions containing a mixture of active ingredients may be prepared by dissolving the gastro-resistant solids contained in the granulated solids. It is prepared using a combination of γ-PGA and γ-PGA, which has an average molecular weight ranging from about 5 kDa to about 500 kDa. In some embodiments, the average polymer molecular weight is about 5 kDa to about 100 kDa. In another embodiment, it is about 1 kDa to about 100 kDa.

[0049] The granulated solid is then suspended in an acidic liquid suitable for ingestion. The granulated food may be an acidic liquid food or liquid nutritional supplement. The pH of the solution is adjusted by the The pH should be below about 6 so that the resulting solid remains stable as a result of the gastro-resistant binder. In one embodiment, the liquid suspension formulation is prepared by dissolving the granulated solids in a well-suspended state. It may also contain thickeners or viscosity enhancers to allow for efficient consumption from the container. For example, in one embodiment, the solid is suspended by shaking or stirring as needed, and then The solids may have a settling time of greater than about 5 seconds, or greater than about 15 seconds. Other excipients, such as flavorings, buffers, preservatives, antioxidants, , sweeteners, etc. may be included in the liquid suspension.

[0050] When a liquid dosage form is constituted for use, γ-PGA is generally present in an amount of from about 0.01% by weight to about 1 0% by weight, and Zn(II) salts are generally present at concentrations of about 0.001% to about 10% by weight. It is present in a concentration of

[0051] Another method for preparing a liquid dosage form is to prepare particles of a complex of zinc salt and γ-PGA, e.g. For example, to form microspheres, microparticles, granules or other suitable solid form, and to dissolve the particles in the wax. In a preferred embodiment, the particles further comprise a gastro-resistant binder. The coated particles are formulated as a liquid suspension formulation. Wax coating on particles Although the coating promotes the physical integrity of the particle and reduces permeability, the coating still It allows the delivery of a complex of zinc and γ-PGA to the intestine.

[0052] Granules suitable for coating can be prepared according to any of the methods described above. Microspheres or microparticles of zinc salt, γ-PGA and gastro-resistant binder have been used in numerous It can be prepared by any of the methods known in the art, which include the step of forming a single dispersed phase. Single emulsion method, double emulsion method emulsion), polymerization, interfacial polymerization, phase separation and coacervation, spray drying Such microspheres or particulates may be prepared by methods such as drying, spray congealing, solvent extraction, and freeze-drying. The dimensions can range from a few tens of microns to a few thousand microns. One method for preparing macrosphere particles involves the use of a microcrystalline cellulose containing zinc salt and γ-PGA. A mixture of finely divided (e.g., powdered) solids is stirred in a suspension medium, e.g., paraffin oil. and adding a solution of a polymeric gastro-resistant binder to the stirred suspension. Once the microspheres are formed, a non-solvent, such as chloroform, is added to precipitate the microspheres. Addition of a silane to the mixture is then made, which is collected, dried and subsequently coated with wax.

[0053] The wax coating is biocompatible and non-immunogenic, allowing drug entrapment and delivery to the intestinal tract. It is recognized that particles (microspheres, microparticles, granules, etc.) are suitable for: Waxes such as carnauba wax, beeswax, cetostearyl alcohol, etc. may be added according to methods known in the art. For example, the particles may be coated with wax such as white paraffin. The particles were dissolved in ethanol, the solution was cooled to below 45°C, and the particles were then mechanically stirred. Carnauba wax is added to a wax / paraffin oil solution until the particles are coated. The stirring speed and time as well as the temperature of the wax solution can be adjusted to suit the wax coating. The thickness of the ring can be adjusted to modify the ring thickness.

[0054] Wax-coated zinc salt and gamma-PGA particles are formulated as a liquid suspension for administration. The coated zinc / γ-PGA particles are present in the final compounded suspension at a concentration of about 5 wt. Typically, liquid suspension formulations contain a suspending polymer, a viscosity agent, and and a buffering agent. The formulation may further include one or more of a sweetener, a flavoring agent, and / or a preservative. That's fine.

[0055] Suspension polymers include xanthan gum, carbomer, microcrystalline cellulose, carboxymethyl cellulose and sodium carboxymethylcellulose, They can be used alone or in any combination. Other similar agents may also be used. In total, the suspension polymer component contributes to the final formulation. It is present in the mixture at about 0.02% by weight to about 5% by weight.

[0056] Viscosity agents include glycerin, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. The surfactant may be selected from the group consisting of cellulose, povidone, guar gum and locust bean gum. , which can be used alone or in any combination. Other similar agents known in the art may also be used. In total, the viscosity agent component contributes to the final formulation. It is present in the composition at about 0.05% by weight to about 50% by weight.

[0057] The buffer may be a phosphate buffer, an acetate buffer, a lactate buffer, a citrate buffer or a predetermined Other nutritionally acceptable buffering agents having a range of buffering capacities may be selected. The buffer is adjusted to have a pH of about 6 or less. In some embodiments, the pH is about 3 to 5. In some embodiments, the pH is about 6. In other embodiments, the pH is about 4.5 to 5. In yet another embodiment, the pH is 3-5.

[0058] Sweeteners include sucrose, invert sucrose, xylitol, sorbitol, and maltitol. , aspartame, saccharin and sucralose, which may be selected from They may be used alone or in any combination. Similar agents may also be used. In total, the sweetener component will be about 5% in the final formulation. It can be present at 50% to about 40% by weight.

[0059] The flavoring agent may be any pharmaceutically acceptable flavoring agent or food or supplement flavoring agent known in the art. Can be selected from any drug used in pharmaceutical formulations and is consistent with industry practice The amount of hydroxybenzoates that can be added to the final formulation can be determined by the following formula:

[0060] Preservatives include sodium benzoate, methylparaben, propylparaben, benzyl alcohol ethanol, potassium sorbate and citric acid, which may be selected from or any combination may be used in the final formulation in amounts consistent with industry practice. Other similar agents known in the art may also be used. can.

[0061] Exemplary formulations and methods for preparing liquid dosage forms according to some embodiments of the present invention are described below. These are provided below in Examples 5 and 6, respectively. Medication and Administration The oral dosage forms described herein are useful for people who need or need to supplement zinc taken in through their diet. The effective amount of zinc can be administered to a person who desires it to provide an effective amount of zinc. The amount of zinc absorbed by humans is sufficient to alleviate zinc insufficiency or deficiency. Achieving an effective amount will depend on the characteristics of the formulation and may vary depending on the individual's gender. This will vary depending on the individual, age, condition and genetic makeup, e.g. genetic causes or malabsorption Individuals with insufficient zinc due to other causes of injury or severe dietary restriction generally have higher High dosage strength formulations or lower dosage combinations Several dosage forms are available to administer effective amounts (generally up to about 100 mg of zinc per day). Individuals who are zinc deficient may take one or more dosage forms per day. More specifically, an effective amount (e.g., up to about 25 mg, or up to 50 mg, or up to 75 mg per day) Multiple dosage forms may be taken together or separately on the same day. The oral dosage form can be administered without regard to mealtime. [Example]

[0062] Example 1: γ-polyglutamic acid-zinc composition The composition of an exemplary embodiment of the present invention is shown in Table 1. The formulation is 25 mg of Zn (Zn 2+ ions). This composition provides the It describes one of many compositions.

[0063] [Table 1]

[0064] Example 2: Method for preparing a gamma-polyglutamic acid-zinc composition Coated tablets having the composition shown in Example 1 were prepared using a wet granulation technique. First, zinc sulfate and gamma-polyglutamic acid are mixed together in a dry state. Microcrystalline cellulose, starch and silicon dioxide are further added to form the dry composition. The ingredients are all further mixed together. The mixed components are transferred to a granulator and mixed with the appropriate A quantity of aqueous ethanol is added and granulation is carried out. is dried at 50 to 70°C, and the granulated composition having a moisture content of less than about 5% is Magnesium stearate is added to the granulated composition, together with The resulting mixture is compressed into tablets. Finally, the tablets are prepared by any method known to those skilled in the art. The coated film is coated with cellulose acetate phthalate using standard techniques such as

[0065] Example 3: γ-polyglutamic acid-zinc solid composition The composition of an exemplary embodiment of the present invention is shown in Table 2. The formulation is 30 mg of Zn (Zn 2+ ions). This composition provides the It describes one of many compositions.

[0066] [Table 2]

[0067] Example 4: Method for preparing a gamma-polyglutamic acid-zinc solid composition Coated tablets having the composition shown in Example 3 were prepared as follows: First, zinc sulfate, gamma-polyglutamic acid, microcrystalline cellulose, HPMC-P( Hydroxypropyl methylcellulose phthalate), maltodextrin and carboxymethylcellulose Dimethylcellulose-calcium are mixed together in a dry state. The mixture is transferred to a granulator, an appropriate amount of 70% aqueous ethanol is added, and wet granulation is carried out. The resulting granulated mixture was dried at up to about 60°C to remove about 3% Granulated compositions having an LOD (loss on drying) of less than 1000 mg / L were obtained. Rosil® and magnesium stearate are added to the granulated composition. The resulting mixture was compressed into tablets. The tablets were Using standard techniques known to those skilled in the art, the isopropyl alcohol of HPMC-P is first In a second step, the sheet is coated with an aqueous solution of HPMC. It was decided.

[0068] Example 5: γ-polyglutamic acid-zinc liquid composition The composition of an exemplary embodiment of the present invention is shown in Table 3. The formulation is 0.68 mg Zn (Zn 2+ This composition provides describes one of many compositions within the scope of the claims.

[0069] [Table 3]

[0070] Example 6: Method for preparing a gamma-polyglutamic acid-zinc liquid composition 1. Preparation of coated ZnPGA microspheres (cZPM). 10 g of sucrose (5% w / v), 45 mg γ-PGA and 19.79 mg zinc sulfate heptahydrate (original 200 mL of water containing 4.5 mg of pure Zn was prepared and freeze-dried. The resulting powder is then finely divided and contains up to 5% corn starch. The mixture was ground in a 1:4 ratio with sucrose and passed through a No. 50 US standard stainless steel sieve (4 The powder was then passed through a 400 mL beaker. The mixture was stirred in a high torque stirrer (Type RXR 1, Caframo, Wyoming, Ontario) mounted on a 44mm polyethylene Dispersion was achieved by stirring with a three-blade paddle at 260 rpm. 10% (w / v) hydroxypropyl methylcellulose in acetone-95% ethanol (9:1) HPMC-Phthalate was added. Stirring was continued for 5 minutes. This resulted in the formation of microspheres, and then 75 mL of chloroform was added. The suspension medium is decanted and the microspheres are briefly soaked in 75 mL of chloroform. The microspheres were resuspended and air-dried at ambient temperature. Once dry, the microspheres were coated with carnauba wax. Specifically, 1 g of carnauba wax was dissolved in 200 mL of white paraffin oil. The wax-paraffin solution was melted at 70°C and cooled to less than 45°C. The prepared microspheres were added to the solution and suspended for 15 minutes with constant stirring. The wax solution is then decanted and the microspheres are left to absorb excess wax solution. The coated ZnPGA microspheres (cZPM) were obtained by collecting them on filter paper.

[0071] 2. Preparation of liquid suspension solution of coated ZnPGA microspheres (cZPM). Ingredients: 0.3 g xanthan gum (e.g., as a suspending polymer); 0.3 g Guar gum (e.g., as a thickener); 10g xylitol (e.g., as a sweetener); 0 0.5g citric acid buffer (e.g., as a buffer); 0.1g limonene (e.g., as a flavoring agent) 0.025 g of potassium sorbate (e.g., as a preservative) in 78.7 mL of water The pH of the aqueous solution was adjusted to pH 4.5, and then 10 g of cZPM was added. , and suspended in an aqueous solution to obtain a liquid suspension of cZPM.

[0072] Although the foregoing invention has been described in detail and by way of example and illustration, those skilled in the art will readily appreciate that the present specification It is to be understood that the scope of the compositions and methods disclosed herein and encompassed by the claims is Deaf.

Claims

1. 1. A composition for use as a pharmaceutical for treating zinc deficiency or zinc insufficiency, formulated as a solid dosage form for oral administration of zinc, the composition comprising 10% to 40% by weight of gamma-polyglutamic acid having a number average molecular weight in the range of 5 kDa to 300 kDa, a zinc salt, wherein the amount of zinc present per solid dosage form is 1 mg to 100 mg, and a gastro-resistant material.

2. 10. The composition of claim 1, wherein the solid dosage form is prepared by a process comprising granulating a mixture comprising the gamma-polyglutamic acid and the zinc salt.

3. 3. The composition according to claim 1, wherein the gamma-polyglutamic acid has a number average molecular weight in the range of 50 kDa to 100 kDa.

4. 4. The composition of claim 1, wherein the zinc is present in an amount of 1 mg to 50 mg per solid dosage form.

5. The composition of any one of claims 1 to 4, wherein the solid dosage form is a tablet or a capsule.

6. The composition according to any one of claims 1 to 5, wherein the gastroresistant material is included in the composition as a gastroresistant binder and / or an outer gastroresistant coating.

7. The composition according to any one of claims 1 to 6, further comprising one or more excipients selected from fillers and / or binders and / or disintegrants.

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