阅读说明：本技术 用于治疗叶酸缺乏和早孕反应的方法和产品 (Methods and products for treating folate deficiency and early pregnancy response ) 是由 T·P·卡斯托尔 于 2019-12-05 设计创作，主要内容包括：本发明的实施方案涉及治疗叶酸缺乏和早孕反应的制剂和方法。该剂型具有有效量的叶酸和有效量的姜醇成分,以抑制恶心和/或胃部不适并促进血细胞生成。(Embodiments of the invention relate to formulations and methods for treating folate deficiency and early pregnancy reactions. The dosage form has an effective amount of folic acid and an effective amount of a gingerol component to inhibit nausea and/or gastric discomfort and promote hematopoiesis.)

1. A dosage form for treating folate deficiency and early pregnancy reactions comprising an effective amount of folic acid selected from vitamin B-9 in natural and synthetic forms, and mixtures thereof, and a zingiberol ingredient in an amount effective to inhibit nausea and/or gastric discomfort, said vitamin B-9 being one of a vitamin B complex, said zingiberol ingredient being selected from the group consisting of zingiberol compounds comprising 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 6-shogaol, 8-shogaol and 10-shogaol, and mixtures thereof, as separate ingredients.

2. The dosage form of claim 1, further comprising an oil base, wherein the folic acid is dispersed in the oil base as a solid suspension and the gingerol component is dissolved in the oil base.

3. The dosage form of claim 2, wherein the oil base is held in a soft gelatin capsule.

4. The dosage form of claim 1, wherein the gingerol component is an extract from a ginger compound containing natural sources.

5. The dosage form of claim 1, wherein the gingerol component is used to wet the powder of folic acid to form a gingerol-wetted folic acid powder.

6. The dosage form of claim 5, wherein the gingerol-wetted folic acid powder is compressed into a tablet.

7. The dosage form of claim 5, wherein the gingerol-wetted folic acid powder is encapsulated.

8. The dosage form of claim 1, wherein the folic acid and gingerol are dissolved or suspended in a solution.

9. The dosage form of claim 1 wherein the folate is present at 400 and 800 mcg of folate.

10. The dosage form of claim 1, wherein the gingerol component is present in an amount effective to promote hematopoiesis.

11. A method of treating early pregnancy reactions comprising administering a dosage form comprising an effective amount of folic acid selected from vitamin B-9 in natural and synthetic forms, and mixtures thereof, and an effective amount of a gingerol component to inhibit nausea and/or gastric discomfort, the vitamin B-9 being one of a vitamin B complex, the gingerol component being selected from a gingerol compound comprising 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 6-shogaol, 8-shogaol, and 10-shogaol, as separate components, and mixtures thereof.

12. The method of claim 11, wherein the dosage form has an oil base, wherein the folic acid is dispersed in the oil base as a solid suspension and the gingerol component is dissolved in the oil base.

13. The method of claim 12, wherein the oil base is held in a soft gel capsule.

14. The method of claim 11, wherein the gingerol fraction is an extract from a ginger compound containing natural sources.

15. The method of claim 11, wherein the gingerol component is used to wet the powder of folic acid to form a gingerol-wetted folic acid powder.

16. The method of claim 15, wherein the gingerol-wetted folic acid is compressed into a tablet.

17. The method of claim 15, wherein the gingerol-wetted folic acid is encapsulated.

18. The method of claim 11, wherein the folic acid and gingerol are dissolved or suspended in a solution.

19. The method of claim 11 wherein the folate is present at 400 and 800 mcg of folate.

20. The method of claim 11, wherein the gingerol component is present in an amount effective to promote hematopoiesis.

Technical Field

Embodiments of the invention relate to articles of manufacture and methods in the form of formulations for treating early pregnancy reactions.

Background

An early pregnancy response is a condition in which a pregnant woman experiences nausea, particularly in the first trimester of pregnancy. Various drugs have been used in the past to treat maternal and fetal deficiencies during pregnancy. These include folic acid. These drugs are also associated with nausea and gastric discomfort (upset stomach).

There is a need for improved formulations that do not cause gastric discomfort (gastropathic stress) and nausea.

Summary of The Invention

Embodiments of the present invention relate to formulations and methods for treating early pregnancy reactions and folate deficiency. One embodiment of the invention relates to a dosage form for treating folate deficiency and early pregnancy response. The dosage form has an effective amount of folic acid and a gingerol component (gingerol composition) in an amount effective to inhibit nausea and/or gastric discomfort. The folic acid is selected from vitamin B-9 (one of vitamin B complex) in natural form and synthetic form. The gingerol component is selected from the group consisting of gingerol compounds including 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 6-shogaol, 8-shogaol and 10-shogaol, and mixtures thereof, as a single component (single composition).

A dosage form of the invention further comprises an oil base, wherein the folic acid is dispersed in such oil base as a solid suspension, and the gingerol component is dissolved in the oil base. The oil base with folic acid and gingerol content can be administered orally in liquid form or held in a soft gelatin capsule (gel cap).

Other embodiments of the invention are characterized as tablet and capsule formulations. By way of non-limiting example, one dosage form is characterized as a gingerol composition that is used to moisten a powder of folic acid to form a gingerol-moistened folic acid powder. The gingerol-wetted folic acid powder is compressed into tablets or filled into capsules.

Another embodiment features a dosage form wherein the folic acid and the gingerol are dissolved or suspended in a solution. The solution is administered orally in liquid form.

The gingerol fraction can be synthesized or is an extract from a ginger compound containing natural sources. By way of non-limiting example, preferred ginger compounds include gingerol and shogaol found in extracts from ginger (zingiber officinale). The preferred gingerol component is present in an amount effective to promote hematopoiesis.

For each dosage form, folic acid was present in 400-800 milligrams (mcg) of folic acid.

A further embodiment of the present invention relates to a method of treating folate deficiency and early pregnancy response comprising the steps of: a dosage form is administered comprising an effective amount of folic acid and an effective amount of a gingerol component to inhibit nausea and/or gastric discomfort. The gingerol component is selected from the group consisting of gingerol compounds comprising 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 6-shogaol, 8-shogaol and 10-shogaol, and mixtures thereof, as individual components. The folic acid is selected from vitamin B-9 (one of vitamin B complex) in natural form and synthetic form.

Dosage forms can take many different forms, including emulsions, dispersions, or solutions in oil bases, for administration in oral liquid form or held in soft gelatin capsules. The dosage form may comprise capsules and tablets.

For adults, the dosage form preferably has 400-800 mcg of folic acid.

The preferred gingerol component is present in an amount effective to promote hematopoiesis. Thus, the gingerol fraction should address folic acid-induced nausea and stomach upset, and synergistically promote hematopoiesis to treat early pregnancy reactions.

These and other features and advantages of the present invention will become apparent to those skilled in the art upon review of the following detailed description when taken in conjunction with the several drawings.

Brief Description of Drawings

FIG. 1 depicts a dosage form embodying features of the invention;

FIG. 2 depicts a dosage form in cross-sectional form embodying features of the invention;

FIG. 3 depicts a dosage form embodying features of the invention; and

fig. 4 depicts an apparatus for preparing a gingerol composition.

Detailed Description

Embodiments of the invention will now be described in detail with respect to formulations and methods for treating folate deficiency and early pregnancy reactions, in terms of the best mode of the inventors' current practice of the invention. The best mode may change over time as new considerations become known or available. Variations and modifications are also made to the embodiments of the invention, such that the present teachings and descriptions should not be considered as limiting.

One embodiment of the present invention relates to a dosage form for the treatment of folate deficiency and early pregnancy response. Dosage forms embodying features of the invention are designated by numerals 61a, 61b and 61c, which are depicted in figures 1, 2 and 3. Fig. 1 depicts a tablet 61a dosage form. Fig. 2 depicts a cross-sectional form of a soft gelatin capsule 61b dosage form. Also, fig. 3 depicts a solution 61c dosage form. Other dosage forms not exemplified are, by way of non-limiting example, capsules, powders for reconstitution, lozenges, and the like.

Each dosage form (tablet 61a, soft capsule 61b, and solution 61c) has an effective amount of folic acid and an effective amount of gingerol composition to inhibit nausea and/or gastric discomfort. The folic acid is selected from vitamin B-9 (one of vitamin B complex) in natural form and synthetic form. Methods of making folic acid are known, and compositions are available from numerous sources. For adults, the dosage form preferably has 400-800 mg folic acid.

The gingerol component is selected from the group consisting of gingerol compounds comprising 6-gingerol, 8-gingerol, 10-gingerol, 12-gingerol, 6-shogaol, 8-shogaol and 10-shogaol, and mixtures thereof, as individual components. One preferred extract has 6-gingerol, 8-gingerol, 10-gingerol and 6-gingerol, wherein 6-gingerol and 6-gingerol define a ratio and the ratio of 6-gingerol to 6-gingerol is from 0.04 to 0.40. While applicants do not wish to be bound by any theory, it is believed that the ratio of 6-shogaol to 6-gingerol improves the efficacy of the extract in treating nausea.

A further aspect of the invention relates to an extract of ginger rhizome (ginger rhizome), wherein the ginger rhizome has an initial mass and the extract has a mass associated with one or more of the following 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol. The ratio of the total mass of 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol to the initial mass is 20-40%.

Additional aspects of the invention relate to extracts having 15-25% 6-gingerol, 1-5% 8-gingerol, 1-5% 10-gingerol, and 1-5% 6-shogaol.

Each dosage form (e.g., tablet 61a, soft capsule 61b, and solution 61c) has a dose of gingerol composition, and in one aspect, the dose is in the range of 20-40 mg of ginger rhizome extract. The amount of extract preferably has a combined gingerol and shogaol of 4.00-14 mg.

An effective amount of folic acid and an effective amount of the gingerol fraction can be divided into two or more dosage forms to address the specific need for a greater amount of folic acid. For example, without limitation, a person with a greater demand for folic acid may take two dosage forms, such as tablet 61a, soft capsule 61b, and solution 61 c. The amount of gingerol component is preferably an amount that accounts for the general nausea and stomach upset associated with folic acid therapy. The gingerol component can also be present in an amount effective to promote hematopoiesis.

Turning now to fig. 1 and dosage form 61a, as depicted, the dosage form comprises a circular tablet. However, one skilled in the art will appreciate that tablets may be formed into many shapes. Tablet 61a has an effective amount of folic acid to treat folate deficiency. An example of an effective amount is 500 mcg folic acid. This amount (folic acid) is moistened with an effective amount of the extract having a gingerol content of 4.00-14 mg. The gingerol fraction can also be used to protect folic acid from oxidation. Folic acid can be combined with conventional and customary excipients, diluents, binders and lubricants (e.g., talc, lactose, starch, stearic acid, and the like) for tablets to facilitate absorption of the gingerol component and to provide a compressible bulk formulation (bulk formulation) mass that can be compressed into tablets. The bulk formulation may also be encapsulated (not shown) in a manner known in the art.

Turning now to fig. 2 and dosage form 61b, as depicted, the dosage form includes a soft capsule having an ovoid shape. However, those skilled in the art will appreciate that other shapes for the soft capsule may be formed. The soft capsule comprises an outer gel surface 65 and an inner liquid 67. The exterior surface 65 is known in the art and need not be described further herein. The internal liquid comprises a suspension of folic acid in an amount effective to treat folate deficiency. An example of an effective amount is 500 mcg folic acid. This amount (folic acid) is suspended in an effective amount of the extract having a gingerol content of 4.00-14 mg, maintained in an oil base. The gingerol fraction and the oil base can also be used to protect folic acid from oxidation.

One embodiment features an oil having an antioxidant, i.e., the antioxidant is dissolved or suspended in the oil. One antioxidant is tocopherol. Preferred formulations have an oil containing one or more emulsifiers. The emulsifier promotes bioavailability and maintains the other components of the formulation in an oil base. Preferred emulsifiers are selected from one or more of the following agents: lecithin, and short chain triglycerides, medium chain triglycerides and long chain triglycerides. The preferred oil is olive oil.

Processes and methods for loading oil with suspended folic acid and dissolved gingerol content are known in the art.

Turning next to fig. 3 and dosage form 61c, a solution is depicted in cross-section as indicated by the numeral 71. The solution is held in a separate application cup 73 sealed with a removable lid 75. Those skilled in the art will appreciate that the solution 71 may be contained in other containers for dispersion and application, including, by way of example and not limitation, a dropper, a jar with or without an application cup, a pouch, and the like. The solution comprises a base fluid, such as water, in which an effective amount of the gingerol component and the folic acid particles are maintained as a suspension in an emulsion. The user is instructed to shake or mix the contents sufficiently.

The dosage forms are used to treat early pregnancy reactions and folate deficiency by orally administering each dosage form (e.g., tablet 11a, soft capsule 11b, and solution 11c) to provide folate. Folic acid is normally ingested one to three times a day. The gingerol compounds prevent nausea and stomach upset and promote hematopoiesis. Wetting the folic acid with an oil-based and/or gingerol fraction delays absorption, causes less gastric discomfort, and prevents oxidation of the folic acid composition.

One preferred gingerol fraction is formed from dried powdered biomass of ginger rhizome. The dried biomass is placed in a vessel with carbon dioxide under supercritical, near-critical or critical conditions to form a saturated biomass powder. Separating carbon dioxide from the biomass to form a carbon dioxide fluid extract containing a composition of gingerol and shogaol.

Preferably, the carbon dioxide is maintained at a temperature of 20-50 ℃ and a pressure of 1000 to 4000 psi. Preferably, the carbon dioxide has a modifier in the sense that the modifier is carried in the carbon dioxide in the nature of dissolved constituents. Preferred modifiers are alcohols, such as ethanol.

Aspects of the present invention employ materials referred to as supercritical, critical or near critical fluids. The material becomes a critical fluid at a temperature equal to its critical temperature and critical pressure. The material becomes a supercritical fluid at or above both its critical temperature and critical pressure. The parameters of critical temperature and critical pressure are the inherent thermodynamic properties of all sufficiently stable pure compounds and mixtures. For example, carbon dioxide becomes a supercritical fluid under conditions of its critical temperature equal to or exceeding 31.1 ℃ and its critical pressure of 72.9 atm (1,070 psig). In the supercritical fluid region, normally gaseous species (e.g., carbon dioxide) become dense phase fluids, which have been observed to exhibit greatly enhanced solvating forces. At a pressure of 3,000 psig (204 atm) and a temperature of 40 ℃, carbon dioxide has a density of about 0.845 g/cc and behaves much like a non-polar organic solvent, with a dipole moment of zero debye.

Supercritical fluids exhibit a wide range of solvating forces, as their density is strongly dependent on temperature and pressure. A temperature change of tens of degrees or a pressure change of tens of atmospheres can change the solubility of a compound in a supercritical fluid by an order of magnitude or more. This feature allows fine tuning of solvation forces and fractionation of mixed solutes. Selectivity of the non-polar supercritical fluid solvent can also be enhanced by the addition of compounds known as modifiers (also known as entrainers or co-solvents). These co-solvents are usually somewhat polar organic solvents such as acetone, ethanol, methanol, dichloromethane or ethyl acetate. Varying the ratio of co-solvents allows for a wide range of variation in solvent power.

Supercritical, near-critical, and critical fluids can exhibit liquid-like densities while still retaining high diffusivity and low viscosity gas-like properties. The latter increases the mass transfer rate and significantly reduces the processing time. In addition, the ultra-low surface tension of the supercritical fluid allows for easy penetration into the microporous material, increasing extraction efficiency and overall yield.

A material in a condition adjacent to its supercritical state will have properties similar to those of the substance in the supercritical state. These so-called "near critical" fluids may also be used in the practice of the present invention. For the purposes of the present invention, a near critical fluid is defined as the following fluids: which is (a) at a temperature between its critical temperature (Tc) and 75% of its critical temperature and at a pressure of at least 75% of its critical pressure, or (b) at a pressure between its critical pressure (Pc) and 75% of its critical pressure and at a temperature of at least 75% of its critical temperature. In this definition, pressure and temperature are defined on an absolute scale (e.g., K and psia). For simplicity of terminology, materials utilized under supercritical, near-critical, or exactly at their critical points with or without polar co-solvents will be collectively referred to as "SCCNC" fluids or as "SFS".

SCCNC fluids can be used for fractional extraction and manufacture of highly purified gingerols and shogaols.

Embodiments of the present invention relate to methods of using supercritical fluids to isolate and manufacture gingerols for use as therapeutic agents in the treatment of nausea and vomiting.

The method and apparatus of the present invention will be described with respect to fig. 4, which fig. 4 depicts in diagrammatic form a ginger fractionation apparatus, generally designated by the numeral 11.

Polarity-directed SCCNC fractionation can be performed on dry and fresh ginger powder. SCCNC CXF fractionation can be performed on an automated extractor or a manual version thereof. As shown in FIG. 4, this is a dual pump system, employing for pure critical fluids (e.g., CO)₂) And a syringe pump 31 for a modifier (e.g., ethanol).

Ginger powderAfter being loaded into the cartridge on the cartridge holder 13, the fractionation sequence may be started. For example, the system can be brought to 3,000 psig and 40 ℃ with pure CO₂The extraction is carried out for 10 minutes. This fraction will be collected in ethanol in a glass vial (numbered 19 in fig. 4). The extraction parameters are then set to: supercritical CO₂Extraction was carried out in steps of 5 vol%, 10 vol%, 20 vol%, 30 vol% and 40 vol% at 3,000 psig extraction temperature of 40 ℃ with ethanol as co-solvent, each step being 10 min. Each biomass sample will produce 6 fractions and the fractions are collected in ethanol in separate glass vials. Each fraction will be dried under vacuum in a SpeedVac and analyzed by HPLC for gingerol, zingerone and shogaol content. Providing the highest combined content of gingerol and shogaol and a ratio of 6-gingerol to 6-shogaol of between 0.04 and 0.4 is advantageous for producing larger quantities.

Example (b):

example 1: fractionation of ginger rhizome

Biomass:ginger (ginger)Zingiber officinale) Biomass (fresh and dried) was obtained from brazilian reputable suppliers. The material was shipped iced by overnight freight to our facility in Woburn, MA. Upon receipt, registering the biomass sample; the dried biomass was stored under dry, low humidity conditions and fresh biomass was stored at 4 ℃. The samples were ground to a fine powder and extracted with different solvents (ethanol, dichloromethane, chloroform and hexane) to determine the gingerol content of the material by HPLC analytical techniques. The underground biomass samples were used for cultivar identification and sent to outside contractors for heavy metal, herbicide and pesticide analysis. A small sample of the voucher was retained.

Ginger powder:the dried ginger roots were cut into pieces and dried in a convection oven at 37 ℃ for 24 hours to remove moisture. The biomass is then ground to a fine powder in a plate hammer mill. A sample of this fines is also extracted by conventional techniques to reconstitute dried and ground ginger (b)Zingiber officinale) Biomass gingerols and shogaolsPhenol content. The biomass powder was labeled and stored at-20 ℃.

Fresh ginger roots were also cut into pieces and dried in a VirTis shelf freeze dryer for a period of 24 hours to remove all moisture and humidity. The biomass is then ground to a fine powder in a plate hammer mill. A sample of this fines is also extracted by conventional techniques to reconstitute dried and ground ginger (b)Zingiber officinale) The gingerol and shogaol content of the biomass. The biomass powder was labeled and stored at-20 ℃.

Ginger extract:polarity-directed SCCNC fractionation was performed on dried and fresh ginger powder. As shown in FIG. 4, this is a dual pump system, employing critical fluid (e.g., CO) for purity₂) And a syringe pump 31 for a modifier (e.g., ethanol).

The data indicate that the following percentages of gingerol and shogaol were obtained. The ratio of 6-shogaol and 6-gingerol is defined, and the ratio of 6-shogaol to 6-gingerol is 0.04 to 0.40. While applicants do not wish to be bound by any theory, it is believed that this ratio of 6-shogaol to 6-gingerol improves the efficacy of the extract in treating nausea.

The ginger rhizome has an initial mass, and the extract has a mass associated with one or more of the following 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol. The ratio of the total mass of 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol to the initial mass is 20-40%.

The extract is characterized as having 15-25% 6-gingerol, 1-5% 8-gingerol, 1-5% 10-gingerol and 1-5% 6-shogaol. The extracted gingerols and shogaols define a total biomass percentage in the range of about 10-15% to about 25-35%.

Example 2: tablet formulation of gingerol compound and folic acid

This example will provide a tablet formulation of folic acid and a gingerol compound.

Each tablet contained:

folic acid 500 mcg

Gingerol extract 4.0-14 mg

Olive oil (the amount is used for dissolving gingerol extract)

Sterotex (amount used to bind folic acid) approximately 2.00 mg

Combining the gingerol extract with olive oil to produce a solution, slowly combining and mixing with folic acid powder and Sterotex to form a compressible solid mass, and compressing the compressible solid mass into a tablet form.

Example 3: soft capsule preparation of gingerol compound and folic acid

Each soft capsule contains:

folic acid 500 mcg

Gingerol extract 4.0-14 mg

Olive oil (the amount is used for dissolving gingerol extract)

Tocopherol (as preservative)

Lecithin

Medium chain triglycerides

The gingerol extract, the desired tocopherols, lecithin and medium chain triglycerides are dissolved in olive oil to form a gingerol-olive oil product. Dispersing folic acid in the form of a fine powder in the gingerol-olive oil product to form a folic acid suspension. The folic acid suspension is filled into soft capsules known in the art.

EXAMPLE 4 solution of gingerol Compound and Folic acid

Each liquid dose (5 ml) of solution contained:

folic acid 500 mcg

Gingerol extract 4.0-14 mg

Olive oil (the amount is used for dissolving gingerol extract)

Tocopherol (as preservative)

Lecithin

Medium chain triglycerides

The gingerol extract, the desired tocopherols, lecithin and medium chain triglycerides are dissolved in olive oil to form a gingerol-olive oil product. Dispersing folic acid in the form of a fine powder in the gingerol-olive oil product to form a folic acid suspension. The folic acid suspension was placed in a suitable liquid dispersion vessel and shaken well as indicated.

Example 5: capsule preparation of gingerol compound and folic acid

This example will provide a capsule formulation of folic acid and a gingerol compound.

Folic acid 500 mcg

Gingerol extract 4.0-14 mg

Olive oil (the amount is used for dissolving gingerol extract)

Sterotex (amount used to bind folic acid) approximately 2.00 mg

The gingerol extract is combined with olive oil to produce a solution, slowly combined and mixed with folic acid powder and Sterotex to form a powder mass, and the powder mass is filled into appropriately sized capsules in a manner known in the art.

In each of the above examples relating to dosage forms, all or a portion of the folic acid can be readily replaced with an equal amount of 400-800 mg folic acid.

Many variations and modifications may be made to the dosage form in light of particular needs. Other dosage forms may prefer a liquid to be administered at a lower dose of folic acid by dropper or the like. The gingerol component, which may or may not be oil-based, with the gingerol component can be emulsified and the emulsion maintained in an aqueous medium.

Especially for dosage forms intended for administration as liquids, the use of flavoring agents to improve patient acceptance is useful.

Thus, the present invention has been described in detail wherein a dosage form having a gingerol component addresses folic acid (induced) nausea and stomach upset, and synergistically promotes hematopoiesis to treat early pregnancy reactions. The description is directed to the best mode presently contemplated, and the inventors' opinion regarding such best mode may vary over time, and may make changes and modifications to the embodiments of the present invention. Accordingly, the description is not to be taken in a limiting sense, and the invention is intended to include the subject matter of the appended claims and their equivalents.

It is intended that all matter contained in the foregoing description shall be interpreted in an illustrative and not a limiting sense.