Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7135—Compounds containing heavy metals
  • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

• This invention is directed to dry powder formulations for use as pharmaceuticals or vitamin/mineral supplements which are free of conventional fillers, lubricants and other excipients, and in particular to such compositions 0 which exhibit excellent flow, compressibility and other cha acteristics.
• dry powder encapsulatable formulations by the addition of significant proportions, e.g., from about 10 to 85% by Q weight thereof, of various lubricants such as talc, silica (sand), stearic acid, magnesium stearate or glyceryl mon- ostearate (soaps), Carbowax, and/or other fillers and excipients to impart the necessary physical characteris ⁇ tics thereto.
• various lubricants such as talc, silica (sand), stearic acid, magnesium stearate or glyceryl mon- ostearate (soaps), Carbowax, and/or other fillers and excipients to impart the necessary physical characteris ⁇ tics thereto.
• talc silica (sand), stearic acid, magnesium stearate or glyceryl mon- ostearate (soaps), Carbowax, and/or other fillers and excipients to impart the necessary physical
• tablet formulations typically contain one or more binders to insure cohesion of the tableted formulation; such binders include, for .example, proteins such as gelatin, water-soluble casein derivatives such as sodium caseinate, water-soluble gums such as gum acacia, tragacanth or the like, or water- 5 soluble cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, sodium carboxy ethyl cellulose, or the like. (Cooper, J. , Tableting research and technol ⁇ ogy, Journal Pharmaceutical Sciences, J5T:1511-1555, 1972).
• binders include, for .example, proteins such as gelatin, water-soluble casein derivatives such as sodium caseinate, water-soluble gums such as gum acacia, tragacanth or the like, or water- 5 soluble cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, sodium carboxy ethyl cellulose, or the like.
• OMP Dry powder encapsulated or tableted formulations incorporating such lubricants, fillers, binders and/or other excipients as described hereinabove are disclosed, for example, in Stoyle et al U.S. Patent No. 3,293,132; Dines et al U.S. Patent No. 3,518,345; Cavalli U.S. Patent No. 3,584,114; and Magid U.S. Patent No. 3,740,432.
• a substantial proportion of the population may exhibit allergic or other acute noxious reactions to var ⁇ ious of the lubricants, fillers, binders or other exci ⁇ pients utilized in encapsulated or tableted pharmaceuti ⁇ cals or vitamin/mineral supplements.
• vitamin supplements particu ⁇ larly those containing the water-soluble vitamin C (ascor ⁇ bic acid) and B-complex vitamins.
• Ingestion of vitamin C and B-complex vitamin supple ⁇ ments may be necessary because of poor dietary habits and various environmental stresses (physical, psychological, and secondary due to infection, trauma, ischemia, r.adia- tion, chemical exposure or cigarette or alcohol con- sumption) .
• tissue ascorbic acid levels of individuals exposed to many of these stresses are decreased by approximately 50%, increasing suscepti ⁇ bility to free radical pathologic reactions, disordered functioning of enzymes which require ascorbic acid as a co-factor (e.g., dopamine beta hydroxylase) , abnormal prostaglandin production, or generally altere blood flows through tissue.
• a co-factor e.g., dopamine beta hydroxylase
• abnormal prostaglandin production e.g., dopamine beta hydroxylase
• some of the complex carbohydrate excipients can: (1) uncouple oxidative phosphor lation, which will decrease the ability of the cells to produce ATP (adenosinetriphos- phate); and (2) inhibit mixed function oxidases in the endoplasmic reticulum which function to detoxify drugs and
• ascorbic acid is a reducing agent which, upon oxidation (e.g., during storage at elevated temperatures), is sus ⁇ ceptible to discoloration (see, for example, Magid U.S. Patent No. 3,493,659, column 1, lines 21-23).
• the reduc ⁇ ing characteristics of ascorbic acid are of particular concern in multi-vitamin supplements containing various of the B-complex vitamins which may be reduced thereby.
• vitamin B 12 may be readily reduced in the
• a fur ⁇ ther object of the invention is to provide such formula ⁇ tions which do not require the presence of large quanti- ties, if any, of conventional lubricants, fillers, binders and/or other excipients and which are not, therefore, sub ⁇ ject to the toxic side effects associated with such addi ⁇ tives.
• FIG. IA is a photomicrograph, taken with a trans ⁇ mitted beam in a light microscope at llOx magnification, 5. or a crystalline ascorbic acid material utilized in the dry powder formulations of the present invention.
• the . crystals are flat, and transparent to the transmitted beam of light;
• FIG. IB is a photomicrograph similar to FIG. IA, 10 taken at the same magnification (llOx), but illustrating a , representative dry powder formulation of the invention in a multi-vitamin composition incorporating the crystalline ascorbic acid material of FIG. IA in admixture with var ⁇ ious powdered B-complex vitamins; 25 FIG. 2A is a scanning electron micrograph, taken at
• FIG. 2B is a scanning electron micrograph similar to FIG. 2A, illustrating the structure of the same ascorbic 20 acid crystals at 510 X magnification;
• FIG. 3A is a scanning electron micrograph similar to FIG. 2A, taken at the same magnification (280 X), but illustrating the structure of the dry powder formulation of FIG. IB; 25 FIG. 3B is a scanning electron micrograph similar to
• FIG. 3A illustrating the structure of the same dry powder formulation shown in FIG. 3A, at 510 X magnification; - .
• FIG. 4A is a scanning electron micrograph similar to " FIG. 2A, taken at 280 X magnification, of finely divided, 30 amorphous ascorbic acid; ⁇ .
• FIG. 4B is a scanning electron micrograph similar to
• FIG. 4A illustrating the structure of the same finely divided, amorphous ascorbic acid shown in FIG. 4A, at 510 X magnification; 'c FIG. 5A is a scanning electron micrograph similar to
• FIG. 4A taken at the same magnification (280 X), but illustrating the structure of a representative dry powder formulation incorporating finely divided, amorphous ascor ⁇ bic acid with the various B-complex vitamins;
• FIG. 5B is a scanning electron micrograph similar to
• FIG. 5A illustrating the structure of the same dry powder formulation shown in FIG. 5A, at 510 X magnification.
• a dry powder formulation suitable for use as a pharmaceutical or vitamin/mineral supplement can be readily and efficiently encapsulated or 5 tableted without requiring the addition of any of the con ⁇ ventional fillers, lubricants, binders or other excipients therein.
• Such a formulation is produced in accordance with the invention simply by mixing the desired effective ingredients with ascorbic acid crystals or crystalline, 10 physiologically acceptable ascorbate salts, in an amount of at least about 5% by weight of the formulation.
• the crystalline ascorbic acid material may thus be employed to reduce the proportions of, or totally eliminate, all other additives and excipients from the formulation.
• the crystalline ascorbic acid or ascorbate salt when added to dry powders the crystalline ascorbic acid or ascorbate salt serves as a "dry lubricant" imparting free flowing characteristics to the resulting composition and facil-' itating encapsulation or tableting thereof in state-of- 20 the-art, high speed encapsulators without caking or stick ⁇ ing. Additionally, the relative fracturability of the crystalline ascorbic acid materials permits the molecular units thereof to be broken up and compositions containing such crystals to be compacted during the encapsulation or 25 " tableting operation.
• the crystalline ascorbic acid or ascorbate salts uti ⁇ lized herein may, because of the specific characteristics of their flat, rhomboid and plate-like multi-layer structures, and the pharmacologically acceptable and bene- 30 ficial properties thereof, be utilized as a dry lubricant -_ ** - * in a wide variety of dry powder formulations utilized as pharmaceuticals or vitamin/mineral supplements.
• a dry lubricant -_ ** - * in a wide variety of dry powder formulations utilized as pharmaceuticals or vitamin/mineral supplements.
• there may be some formulations in which inclusion of the crystalline 5 ascorbic acid materials may not be desirable because of their reducing characteristics and the resulting risk of reductive degradation of particularly unstable materials which may be admixed therewith.
• Such agents include vitamins such as the B-complex vitamins, e.g., thiamine (B ⁇ , riboflavin (B 2 , niacin (B.,), pyridoxine (B g ), cyanocobalamin (B- j -) ' f°lic acid, pantothenic acid, paraminobenzoic acid, inositol, choline, biotin, retinoids, and calciferols; mineral sup ⁇ plements such as selenium, zinc, calcium, magnesium, manganese, chromium and dolomite; other food supplements such as lecithin, yeast, herbs, plankton or plant fiber; or pharmaceutically active agents such as the barbitu- rates, e.g., secobarbital, the phenothiazine tranquili- zers, e.g., chlorpro azine, antibiotics, e.g., tetra- cycline or penicillin, analges
• acetaminophen or aspirin e.g. theophylline
• decongestants e.g., chlorpheniramine or phenylpropanolamine
• cardiovas- cular preparation e.g. , " quinidine or digitalis prepara ⁇ tions; or other compounds such, for example, as beta caro ⁇ tene, canthaxanthin or the like.
• the present invention embraces dry powder formulations which may be broadly useful as either vita- min/ ineral supplements or pharmaceuticals, including pre ⁇ scription drugs and over-the-counter substances, wherein the crystalline ascorbic acid material is utilized to • ⁇ » .impart improved flow and compressibility characteristics ' thereto, even apart from its desirable properties as a vitamin.
• the crystalline ascorbic acid-containing formulations hereof are particularly useful in connection with the preparation of multi-vitamin compositions containing var ⁇ ious of the B-complex vitamins, including vitamin B,.-. It has been found that with the exception of vitamin B,.-. It has been found that with the exception of vitamin B,.-. It has been found that with the exception of vitamin B,.-.
• the B-complex vitamins are adsorbed on the crystal faces of the crystalline ascorbic acid materials, thus forming relatively dense, flat, composite particles. Adsorption of the B-complex vitamins on the relatively
• FIGS. 1 through 3 of the accompanying drawings The dense, flat particles thus formed are best illus- 5 trated in FIGS. 1 through 3 of the accompanying drawings, wherein it may be seen that the B-complex vitamins are adsorbed on the broad flat surfaces of the ascorbic acid crystals without forming irregular clumped aggregates. Comparing FIGS. IA and IB for example, adsorption of the 10 B-complex vitamins on the transparent ascorbic acid crys ⁇ tals of FIG. IA eliminates their transparency (FIG. IB); moreover, it may be seen from FIG. IB that very little of the B-complex is unadsorbed. On the other hand, as illus ⁇ trated in FIGS.
• the B-complex vitamins tend to ⁇ 15 clump with the amorphous ascorbic acid powder; par ⁇ enthetically, it may be noted that not all of the B- co plex material is visible in FIGS. 5A and 5B, a portion being dislodged and lost during vacuum-evaporation prepa ⁇ ration of the specimen since it does not have a surface 0 upon which to be adsorbed.
• the preferred multi-vitamin formulations of the invention desirably incorporate vitamin B, - in the form of relatively large cyanocobalamin crystals which, notwith ⁇ standing the recognized susceptibility of vitamin ⁇ , _ to 5 reductive degradation, are not reduced by the crystalline ascorbic acid ingredient thereof.
• the vitamin B,- I s protected against reduction because of the size, density, rigid crystalline structure, and surface characteristics of the cyanocobalamin crys- 0 tals, which prevent adherence thereof to the ascorbic acid crystals.
• the cyanocobalamin crystals do not adhere to the crystalline ascorbic acid materials.
• the adsorbed "coating" of the B-complex vitamins on the crystalline ascorbic acid additionally serves to shield the crystalline vitamin B ⁇ 2 from reduction by the ascorbic acid ingredient of the multi-vitamin formulation. It may thus be seen that, in the preferred water- soluble multi-vitamin formulations of the invention, the crystallographic and physical properties of the ascorbic acid and the several B-complex vitamins not only improve the flow and compressibility characteristics of the compo ⁇ sition but additionally minimize, if not eliminate, the risk of degradation of the respective constituents and thereby significantly improve the stability thereof.
• the crystalline ascorbic acid materials referred to herein include both ascorbic acid per se, and the physio ⁇ logically acceptable cationic ascorbate salts, e.g., sodium ascorbate, calcium ascorbate, and magnesium ascor ⁇ bate.
• the crystalline ascorbic acid materials are gen ⁇ erally rhomboid shaped, plate-like crystals which may have particle sizes passing anywhere from 200 to 10 mesh screens, crystals of medium-fine grade (30-80 mesh) being particularly preferred.
• the crystals are incorporated in the dry powder formulation in amounts of as little as about 5% to as much as about 90% by weight thereof.
• the crystalline ascorbic acid materials are desirably incorporated in amounts of from about 30 to 80% thereof.
• the crystalline- ascorbic acid materials utilized her ⁇ ein are commercially available substances which may be produced by the hydrogenation of D-glucose to D-sorbitol, followed by the microbial oxidation to L-sorbose, carboxy- lation to diacetone-2-keto-L-gulonic acid, and conversion to ascorbic acid by heating with hydrogen chloride.
• the ascorbate salts may of course be produced directly from the acid, if desired.
• the 5-member ring is substantially planar.
• the material has a monoclinic crystalline structure, usually in plate-like form with occasional needles, four molecules of the ascorbic acid defining a unit cell.
• Two unit cells form pairs in pseudo-symmetrical order, whereby the mole ⁇ cules as well as the unit cells are connected by hydrogen bonding.
• the resultant planar crystals are thus slidable relative to each other, permitting them to act as a dry lubricant to impart free flowability to powders which otherwise tend to cake, stick or clump during encapsula ⁇ tion or tableting thereof.
• the individual ascorbic acid (or ascorbate) crystals are readily fracturable due to the lack of extreme density and strength within the individual crystal structures. It is thus possible to break and com ⁇ pact the individual crystals upon subjecting the dry pow ⁇ der formulations containing the same to compressive forces during encapsulation or tableting.
• the dry powder formu ⁇ lation incorporating the crystalline ascorbic acid mate- rials are thus readily compressible, as well as free flowing.
• the crystalline synthetic ascorbic acid materials utilized in accordance with the present invention are more stable than natural ascorbic acid crystals or the amorphous, fine powder ascorbic acid utilized in conventional multi-vitamin formulations. Materials of these latter types have been described as subject to oxidation upon exposure to air and light (see the Merck Index, 8th Edition, 1968, p. 105).
• the synthe- tic crystalline ascorbic acid utilized in the formulations hereof may, because of the existence of hydrogen bonding in the crystal, be less susceptible to autoxidation to dehydro ascorbic acid and thus exhibit superior stability. It will be understood that the preceding is but one pos- sible explanation of the superior flow, compressibility and stability characteristics of the crystalline ascorbic acid materials incorporated in the dry formulations of the
• the preferred dry powder formulations of the invention incorporate the crystalline ascorbic acid materials, in amounts of from about 30 to 80%, in admixture with other water-soluble vitamins, preferably blends with vitamin B,_ and other B-complex vitamins.
• Particularly preferred multi-vitamin formulations of this type desirably incorporate the following ingredients:
• vitamin B in the form of pure, reduction-resistant cyan ⁇ ocobalamin crystals.
• the crystals thus utilized in the dry powder formulations hereof are needle-shaped, having a dense, strong lattice structure.
• This crystal form exhibits superior resistance to reductive degradation.
• the cyanocobalamin is not readily attracted by electrostatic attraction to the ascorbic acid crystals.
• the B-complex vitamins including vitamin B, ⁇ in the form of the above indicated cyanocabalamin crystals, may thus be admixed with the crystalline ascorbic acid mate ⁇ rials without risk of either reductive degradation of the vitamin B, 2 or oxidative degradation of the other B-complex vitamins.
• Such is of particular importance in the frequent dosing of largedoses of the multi-vitamins.
• vitamin B, ate normally incorporated in such formulations when large dose regimens are utilized the possibility exists of the dosing of clinically significant amounts of degraded
• the dry powder formulations of the invention may be prepared by blending the various constituents thereof in any suitable proportion and manner, dependent on the par ⁇ ticular constitutents thereof.
• the preferred water-soluble multi-vitamin formulations incorporating cyanocobalamin and other B complex vitamins it is pre ⁇ ferred to prepare the mix as follows: (1) triturate the cyanocobalamin crystals with an aliquot of the calcium pantothenate (5-10% of the total pantothenate to be used) to insure uniform dispersion of the microgram quantities of cyanocobalamin in each capsule; (2) mix all the other materials together without the triturate of cyanocobalamin in order to adsorb the other B-complex vitamins without affecting attraction of the cyanocobalamin to the crys ⁇ talline ascorbic acid materials; and (3) add the triturate of cyanocobalamin to the mixture.
• Example 1 Flow Characteristics Of A Dry Powder Formulation Of The Invention
• ascorbic acid crystals (30-80 mesh) 200 grams calcium pantothenate powder 30 grams thiamine hydrochloride powder 10 grams pyridoxine powder 10 grams niacin powder 5 grams riboflavin powder 1 gram cyanocobalamin crystals (99% purity) 50 mg
• the mixture was prepared by (1) triturating the cyan ⁇ ocobalamin with a 5% aliquot of the calcium pantothenate (1.5 grams); (2) mixing all the other materials together without the triturate of cyanocobalamin; and (3) adding the triturate of cyanocobalamin to the mixture. These steps were performed in sequence to insure the uniform dispersion of the cyanocobalamin and also to adsorb the other B-complex vitamins on the crystalline ascorbic acid prior to adding the cyanocobalamin.
• Example 2 A further batch of a dry powder formulation similar to that described in Example 1 was prepared and encapsula ⁇ ted in size 0 capsules, employing the semi-automatic Parke-Davis encapsulator referred to hereinabove.
• the dry powder mixture was prepared as described in Example 1.
• Each size 0 capsule thus filled contained approxi ⁇ mately the following composition: ascorbic acid 570 mg
• TOTAL 720 mg The 720 mg. packing density is to be compared to the normal packing density of 500 g. for similar, conven ⁇ tional formulations in the same size capsule.. It may be seen that the encapsulated formulation of the invention had a more than 40% greater potency than conventional for ⁇ mulations encapsulated in the specified capsule size.
• Example 3 Comparison of Compressibility Of Dry Powder
• Cyanocobalamin (99% pure) crystals 50 mgs (0.2 mm - 0.5 mm length, 0.05 mm - 0.1 mm width)
• the above mixture was hand filled into size 0 cap- sules at a rate of 80 capsules per hour, each capsule con- - . taining about 482 mg. of the mixture.
• niacin powder 5 grams 12.5 mg 10 mg
• Example 2 Flow was determined as in Example 1, in a gravity-feed glass funnel of the same dimensions, whereas compressibility was evaluated in 500 capsule sa - pie hand-filled encapsulation tests. Significantly, the ascorbic acid comprised only 10% of the " total mixture, by weight.
• the flow rate through the gravity-feed funnel system described in Example 1 was 0.8 kg/min. with the funnel at 90° from the horizontal and 0.4 kg/min. at 45° from the horizontal.
• a control blend incorporat- ing identical proportions of each of the above materials save for the substitution of an amorphous finely divided ascorbic acid powder was found to stick within the stem at the point at which the funnel met the stem proper, and could not be fed therethrough at 90° or 45° angles with the horizontal.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=23462101

Family Applications (1)

Country Status (6)

Families Citing this family (23)

Citations (5)

• 1982
  • 1982-04-22 US US06/371,003 patent/US4454125A/en not_active Expired - Lifetime
• 1983
  • 1983-04-20 EP EP83901783A patent/EP0105924B1/en not_active Expired
  • 1983-04-20 DE DE8383901783T patent/DE3382047D1/de not_active Expired - Lifetime
  • 1983-04-20 WO PCT/US1983/000587 patent/WO1983003757A1/en not_active Ceased
  • 1983-04-20 JP JP58501824A patent/JPS59500564A/ja active Granted
  • 1983-04-21 CA CA000426439A patent/CA1209041A/en not_active Expired

Patent Citations (5)

Also Published As

Similar Documents

Legal Events