CA2219035A1 - Fragrances and flavorants - Google Patents
Fragrances and flavorants Download PDFInfo
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- CA2219035A1 CA2219035A1 CA002219035A CA2219035A CA2219035A1 CA 2219035 A1 CA2219035 A1 CA 2219035A1 CA 002219035 A CA002219035 A CA 002219035A CA 2219035 A CA2219035 A CA 2219035A CA 2219035 A1 CA2219035 A1 CA 2219035A1
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- active agent
- proteinoid
- microsphere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/72—Encapsulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/645—Proteins of vegetable origin; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
- A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L9/00—Disinfection, sterilisation or deodorisation of air
- A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
- A61L9/04—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air without heating
- A61L9/042—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air without heating with the help of a macromolecular compound as a carrier or diluent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q13/00—Formulations or additives for perfume preparations
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
Abstract
Compositions useful in the delivery of fragrances and flavorant active agents, and particularly vaporous fragrances and flavorants, are provided. These compositions include a microsphere which includes: (a) the active agent; and (b) (i) a proteinoid, (ii) a modified hydrolyzed vegetable protein wherein the protein is modified with an amino reactive agent, or (iii) a combination thereof. Also contemplated is a method for preparing these compositions wherein the active agent is mixed with the proteinoid of hydrolyzed vegetable protein solution and the proteinoid or modified hydrolyzed vegetable protein is precipitated out of the solution, thereby forming a microsphere containing the active agent. In a further embodiment, the active agent is applied to a substrate.
Description
CA 0221903~ 1997-11-13 WO ~'4~C70 PCTAUS96/10183 FRAGRANCES AND FLAVORANTS
FIELD OF THE INVENTION
The present invention relates to compositions which include fragrances or flavoranls as active agents and to the delivery of such agents.
15 These compositions are in the form of proteinoid or modified hydrolyzable vegetable protein microspheres which can be adapted to release the active agent in specific pH ranges. Methods for the preparation and for the use of such compositions are also disclosed.
Pl oteil loid microspheres have been described for encapsulating pharmaceuticals for oral deliver. (Steiner, et al., U.S. Patent No. 4,925,673).
However, it has now been discovered that other specific active agents can be delivered with proteinoid microspheres.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphic illustration of the head space concentrations of clove oil at various pH's from clove oil containing proteinoid microspheres in comparison with clove oil or clove oil in combination with proteinoids that are 30 not in microsphere form.
Figure 2 is a graphic illustration of the head space concentrations of the components of clove oil at various pH's from clove oil containing ~,roteinoid microspheres in comparison with clove oil or clove oil in the presence of protei"oids that are not in microsphere form.
CA 0221903~ 1997-11-13 SUMMARY OF THE INVENTION
Compositions useful in the delivery of fragrances and flavorant active agents, and particularly vaporous fragrances and flavorants, are provided.
These compositions comprise a microsphere which comprises (a) the active agent; and (b) (i) a proteinoid, (ii) a modified hydrolyzed vegetable protei~) wherein the pro~ein is modified with an amino reactive agent, or (iii) a combination thereof.
Also contemplated is a method for preparing these compositions wherein the active agent is mixed with the proteinoid of hydrolyzed vegetable protein solution and the proteinoid or modified hydrolyzed vegetable protein is precipitated out of the solution, thereby forming a microsphere containing the active agent.
In a further embodi".ent, the active agent is applied to a substrate.
The present invention is suited to the delivery of active agents and fragrances or flavorants which optionally may be in a vaporous form either before or after incorporation into a microsphere. The present compositions incorporate readily available or easy to prepare, inexpensive starting materials.
The formulation methods of the present invention are cost effective for prepari,.g and isolating these co~-positions, are simple to perform, and are amenable to industrial scale for co"---,ercial production.
Active Agents The active agents of the present invention include flavorants and fragrances. Flavorants are compounds or compositions that either increase or enhance an existing taste or that impart a specific taste. Fragrances are compounds or compositions that either increase or enhance an existing smell or odor or that impart a specific agreeable smell or odor. These fragrances and flav~rd" l~ may be solids, liquids, vapors, or any combination thereof .
Furthermore, they may cG""~lelely or partially change state before being incor~,orated into a .-,icrosphere, while inco~l,oraled in a microsphere, or after being partially or completely released from a microsphere. Non-limiting examples CA 0221903~ 1997-11-13 WO ~ CC70 PCT/US96/10183 of fla~ orants and fragrances are clove oil.
Vaporous active agents are those that are at least partially vaporous before incorporation in a microsphere and/or while incorporated in a microsphere.
The compositions of the present invention may include one or more active agents.
Proteinoids Proteinoids are a, lificial polymers of amino acids. An amino acid 10 is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids. Amino acids suitable for use herein includenaturally occurring and synthetic amino acids as well as a- and non a-amino acids. Represe, ~talive, but not limiting, amino acids suitable for use in the present invention are generally of the formula H - N ~R1) - (R2- C) - OH
wherein: R' is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
R2 is C1-C24 alkyl, C2-C24 alkenyl, C3-C~o cycloalkyl, C3-C~o cycloalkenyl, phenyl, naphthyl, (C,-C10 alkyl) phenyl, (C2-C,O
alkenyl) phenyl, (C,-C,O alkyl) naphthyl, (C2-C,O alkenyl) naphthyl, phenyl (C,-C,O alkyl), phenyl (C2-C,O alkenyl), naphthyl (C,-C,O alkyl), or naphthyl (C2-C,O alkenyl);
R2 being optionally substituted with C~-C4 alkyl, C2-C4 alkenyl, C~-C4 alkoxy, -OH, -SH, -Co2R3, C3-C~o cycloalkyl, C3-C~o cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C~-C,O alk)aryl, ar(C,-C,O alkyl) or any combination thereof;
R2 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
The pr~rerled amino acids for use in the present invention are ~-W O ~f"CC70 PCT~US96/10183 amino acids, and most preferably are naturally occurring ~-amino acids. Many amino acids and amino acid esters are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl, USA); Sigma Chemical Co. (St. Louis, M0, USA); and Fluka Chemical Corp. (Ronkonkoma, 5 NY, USA).
Preferred naturally occurring amino acids for use in the present invention as amino acids or components of a peptide are alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, Iysine, methionine, ornithine, 10 phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxy proline, y-carboxyglul~l.,ale, phenylglycine, or 0-phosphoserine. The preferled amino acids are arginine, leucine, Iysine, phenylalanine, tyrosine, tryptophan, valine, and phenylglycine.
Non-limiting examples of non-naturally occurring amino acids for 15 use in the present invention are,6-alanine, a-amino butyric acid, y-amino butyric acid, y-(aminophenyl) butyric acid, a-amino isobutyric acid, citrulline, ~-aminocaproic acid, 7-amino heptanoic acid, ,~-aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, y-glutamic acid, cysteine, ~-lysine, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-20 nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrah~droisoquinoline-3-carboxylic acid, and thioproline.
The proteinoids useful herein preferably are prepared from mixed amino acids. Plerer~ed proteinoids are condensation polymers, and most preferably, are thermal condensation polymers. These polymers may be directed 25 or random polymers. Protei, .oids can be linear, branched, or cyclical, and certain proteinoids can be units of other linear, branched, or cyclical proteinoids.
Special mention is made of diketopiperazines. Diketopiperazines are six member ring compounds. The ring includes two nitrogen atoms and is substituted at two carbons with two oxygen atoms. Preferably, the carbonyl 30 groups are at the 1 and 4 ring positions. These rings can be optionally, and most often are, further substituted.
Diketopiperazine ring systems may be generated during thermal poly",eri~alion or condensation of amino acids or amino acid derivatives.
W 0 9GI~C070 PCTAUS96/10183 (Gyore, J; Ecet M. Proceedings Fourth ICTA ~Thermal AnalysisJ, 1974, 2, 387-394 (1974)). These six ",e,-lbered ring systems were presumably generated by intra-molecular cyclization of the dimer prior to further chain growth or directly from a linear peptide (Reddy, A.V., Int. J. Peptide Protein Res., 40, 472-476 5 (1992); Mazurov, A.A. et al., Int. J. Peptide Protein Res., 42, 14-19 (1993)).Diketopiperazines can also be formed by cyclodimerization of amino acid ester derivatives as described by Katchalski et al., J. Amer. Chem. Soc., 68, 879-880 (1946), by cyclization of dipeptide ester derivatives, or by thermaldehydration of amino acid derivatives and high boiling solvents as described by 10 Kopple et al., J. Org. Chem., 33 (2), 862-864 (1968).
Diketopiperazines typically are formed from a-amino acids.
Rlererably, the a-amino acids of which the diketopiperazines are derived are glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers of any of the foregoing.
Special mention is made of diketopiperazines of the formula R~ ~N~R6 20 wherein R4, R5, R6, and R7 independently are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (Cl-C10alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl(C1-C1O
alkenyl), naphthyl (C1-C10 alkyl), and naphthyl (C1-C10 alkenyl); any of R4, R5, R~, and R7 independently may optionally be substituted with C1-C4 alkyl, C1-C4 25 alkenyl, C1-C4 alkoxy, -OH, -SH, and -CO2R8 or any combination thereof; R8 is hydrogen, C1-C4 alkyl or C1-C4 alkenyl; and any of R4, R5, R6, and R' independently may optionally be interrupted by oxygen, nitrogen, sulfur, or any combination thereof.
The phenyl or naphthyl groups may optionally be substituted.
CA 022l903~ l997-ll-l3 Suitable, but non-limiting, examples of substituents are C1_CB alkyl, C1 C6 alkenyl, C1-C~ alkoxy, -OH, -SH, or CO2R9 wherein R9 is hydrogen, Cl-C~ alkyl, or Cl-C~ alkenyl.
Pl erer~bly, R6 and R~ independently are hydrogen, C1 -C4 alkyl or C1-C4 alkenyl. Special mention is made of diketopiperazines which are pre~er.e.l complexing pert~"ba"L~. These diketopiperazines include the unsubstituted diketopiperazine in which R4, R5, R6, and R' are hydrogen, and diketopiperazineswhich are substituted at one or both of the nitrogen atoms in the ring, i.e. mono or di-N-substituted. Special mention is made of the N-substituted 10 diketopiperazine wherein one or both of the nitrogen atoms is substituted with a methyl group.
Special mention is also made of diketopiperazines of the formula Rl~l~N~
N J~ ll H~
wherein R10 and R1' independently are hydrogen, Cl-C24 alkyl, C,-C24 alkenyl, phenyl, naphthyl, (Cl-Cl0 alkyl)phenyl, (Cl-Cl0 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl (Cl-C10 alkyl), and naphthyl (Cl-Cl0 alkenyl); but both Rl~ and 20 Rll can not be hydrogen; either or both R10 or R11 independently may optionally be substituted with C1-C4 alkyl, C1-C4 alkenyl, C,-C4 alkoxy, -OH, -SH, and -CO2R12 or any combination thereof; R12 is hydrogen, C1-C4 alkyl or C1-C4 alkenyl;
and either or both R10 and R11 independently may optionally be interrupted by oxygen, nitrogen, sulfur, or any combination thereof.
The phenyl or naphthyl groups may optionally be substituted.
Suitable, but non-limiting, examples of substituents are Cl-C~ alkyl, Cl-C6 alkenyl, C1-C~3 alkoxy, -OH, -SH, or CO2R13 wherein Rl3 is hydrogen, Cl-C~ alkyl, or C1-C~ alkenyl. When one of R10 or R11 is hydrogen, the diketopiperazine is mono-carbon-(C)-substituted. When neither R10 nor R1 1 is hydrogen, the CA 0221903~ 1997-11-13 W O 9f~1~C~u PCTAJS96/lû183 diketopiperazine is di-carbon-(C)-substituted.
Pleferably, R10, R1~, or both R'~ and R11, contain at least one functional group, a functional group being a non-hyd, ocarl,on portion responsible for characteristic reactions of the molecule. Simple functional groups are 5 heteroatoms including, but not limited to halogens, oxygen, sulfur, nitrogen, and the like, attached to, the carbon of an alkyl group by a single or multiple bond.
Other functional groups include, but are not limited to, for example, hydroxyl groups, carboxyl groups, amide groups, amine groups, substituted amine groups, and the like.
Preferred diketopiperazines are those which are substituted at one or two of the carbons of the ring with a functional group that includes at leastone carboxyl functionality.
Modified Hvdrolyzed Vegetable Protein Modified hydrolyzed vegetable protei-l is prepared from hydrolyzed vegetable protein. Hydrolyzed vegetable protein is a product which is derived from der~lLed vegetable meal. In practicing the present invention, acid or enzyme hydrolyzed vegetable proteins are useful. The vegetable proteins generally contain titratable carboxylic acid groups (COOH) ranging from about 20 3 to about 8 milliequivalents/g, ~., ererably from about 4 to about 6 milliequivalents/g, and total free amino groups (NH2) ranging from about 3 to about 9 milliequivalents/g, preferc,l~ly ranging from about 4 to about 7 milliequivalents/g NH2. The molecular weight of the hydrolyzed vegetable protein ranges from about 100 daltons to about 2000 Daltons, and preferably 25 from about 200 to about 500 daltons Hydrolyzed vegel~Lle proteii) is available from a variety of commercial sources, such as, for example, Ajinomoto USA, Inc. (Teaneck, NJ);
Central Soya Co., Inc. (Fort~ayne, IN); Champlain Industries, Inc. (Clifton, NJ,);
Archer Daniels Midland (Decatur, IL), A.E. Staley Company, Gunther Products 30 Division, (Decatur, IL), and additional companies listed in "Food Engineering Mastern, an annual publication of Chilton Co., Radnor, PA. A preferred hydrolyzed vegetable protein in practicing this invention is available from Ajinomoto USA under the tradename AJI-EKI. This product is an acid CA 0221903~ 1997-11-13 WO 9~1~70 PCT~US96/10183 hydrolyzed liquid soybean protein which is derived from defatted soybean meal.
Other preferred hydrolyzed soy proteins include PROFAM 781, available from Archer Daniels Midland and PTOT 1550 and MIR-A-FOAM 100 available from A.E. Staley, Gunther Products division.
If desired, a dried protein extract of the hydrolyzed vegetable protein solution may be used to prepare the modified hydrolyzed vegetable protein of the invention. The dried protein extract is preparable by extracting the hydrolyzed vegetable ~.rotei., solution with a suitable solvent, e.g., methanol, followed by evaporating the solvent extract.
The hydrolyzed vegetable protein is modified by an amine reactive agent. Typically the hydrolyzed vegetable protein is modified by acylating or sulfonating at least one free amine group, with an acylating or sulfonating agent which reacts with at least one of the free amine groups present. Suitable, but non-limiting, examples of acylating or sulrGndLi- ,9 agents useful for preparing the 15 modified hydrolyzed vegetable protein emulsifiers of the present invention include acylating and sulfonating agents having the formula:
o R14(--C--X)n or R14--SO2--X wherein R'4 is alkyl or alkenyl, preferably having from 1 to 20 carbon atoms, or aromatic preferably having from 6 to 20 carbon atoms and n is 1 or 2.
The R'4 group can be substituted or unsubstituted, The preferred substituents include C, to C4 alkyl, C, to C4 alkenyl, C, to C4 alkoxy, Co2R'5 wherein R15 is hydrogen, C, to C4 alkyl or C1 to C4 alkenyl.
I'~leferably, R'4 is methyl, ethyl, phenyl, benzyl or naphthyl. More preferably, R14 is phenyl, or acetyl. X is a leaving group. In a reaction in which the substrate molecule becomes cleaved, part of it (the part not containing the carbon) is usually called the leaving group. See Advanced Organic Chemistrv.
2d edition, Jerry March, New York: McGraw-Hill Book (1977), page 187, 30 Typical leaving groups include, but are not limited to, halogens such as chlorine, bromine and iodine.
Examples of the acylating and sulfonating agents for modifying hydrolyzed vegetable protein include, but are not limited to, acyl halides, such CA 0221903~ 1997-11-13 as, for example, acetyl chloride, propyl chloride, benzoyl chloride, phthaloyl chloride, hexahydrophthaloyl chloride, tetrahydrophthaloyl chloride, cyclohexanoyl chloride, sebacoyl chloride, hippuryl chloride and the like; sulfonyl halides, such as, for example, benzene sulfonyl chloride, acetylsulfanilyl chloride, 5 and the like; anhydrides, such as, for example, acetic anhydride, propyl anhydride, benzoic anhydride, maleic anhydride, phthalic anhydride, tetrahydrophthalic anhydride, hexahydrophthalic anhydride, hippuric anhydride and the like. The prerer-ad acylating and sulfonating agents are benzoyl chloride, benzene sulfonyl chloride, cyclohexanoyl chloride, phthalic anhydride,10 tetrahydrophthalic anhydride, and hexahydrophthalic anhydride.
The hydrolyzed vegetable protein is typically modified by first dissolving it in aqueous alkaline solution of a metal hydroxide, e.g., sodium orpotassium hydroxide, and heating at the solution to a temperature ranging from about 50~C to about 70~C, preferably from about 50~C to about 60~C, for a 15 period ranging from about 10 minutes to about 40 minutes, preferably about 15minutes. The amount of alkali employed per mmole of titratable NH2 in the hydrolyzed vegetable protein generally ranges from about 2 to about 3 mmole, and preferably from about 2.2 to about 2.5 mmole. The pH of the solution is generally maintained from about 8 to about 13, preferably ranging from about 20 9 to about 10.
Thereafter, the acylating or sulfonating agent is added to the reaction mixture. The amount of acylating or sulfonating agent in relation to the quantity of hydrolyzed vegetable protei,l employed is based on the equivalents of total free NH2 in the hydrolyzed vegetable protei,-. Thus, from about 0.3 to 25 about 1.2 equivalents of acylating or sulfonating agent are used for each molar equivalent of total NH2 groups in the hydrolyzed vegetable protein, and prefera-bly from about 0.6 to about 1.0 equivalent of acylating or sulfonating agent foreach molar equivalent of groups NH2 groups in the hydrolyzed vegetable ,urotei~).
The modified hydrolyzed vegetable protein is then recovered from the reaction - 30 mixture using standard techniques, such as, for example, precipitation withdilute acid and filtration of the precipitate. See also, PCT Publication No.
W094/14420 (July 7, 1994).
CA 022l903~ l997-ll-l3 W O 9G,~ 70 PCTAJS96/10183 Microspheres The microspheres of the present invention can generally be of a matrix form or the microcapsule form. The matrix form includes both hollow matrix spheres in which the proteinoid forms a matrix shell around a hollow 5 center, and the active agent is distributed throughout the matrix, and a solidmatrix sphere in which the proteinoid forms a circle matrix continuing in which the active agent is distributed. The .nicroc~psule form is one in which the enc~pslJlated active agent either is in a vapor solution, a solid state, or any combination thereof, with the carrier forming a shell around the enc~psl~ated 10 material. The microcapsule form is the form most often taken by the self assembly with the ~Jroteinoids of the present invention. The microspheres can also have the flavor or fragrance adsorbed thereon. The microspheres are preferably non-porous.
Microspheres can be prepared by dissolving the carrier, i.e., 15 proteinoid or modified hydrolyzed vegetable protein in an appropriate solvent and then stimulating self assembly by contacting the carrier solution with a precipitator. Solubility of the carrier can be regulated by the selection of theappropriate amino acid.
Furthermore, the carrier, and therefore, the microsphere 20 compositions of the present invention can be pH adapted to be selectively soluble in specific acidic, basic, or neutral pH ranges.
Compositions which are targeted to an acidic environment can be made selectively soluble at specific ranges of acidic pH. These compositions areprepared with an acid-soluble carrier. The acid-soluble carrier exists largely in 25 the cation form in at least a portion of the pH range from about 1 to about 6.8.
However, outside the selected range, such as for example, at a different acidic pH or above about 6.8 or at selected ranges above pH 6.8, the carrier is largelyunprotonated and insoluble in water. Therefore, the carrier could self assemble to microspheres at a different acidic pH or at a basic or neutral pH, and the 30 active agent in the composition would not be released until the carrier solubilizes upon encountering the selected acidic pH.
Compositions which are to be targeted to an alkaline environment can be made selectively soluble at specific ranges of alkaline pH. These CA 0221903~ 1997-11-13 WO 96~-C7~ PCTAJS96/10183 compositions are prepared with a base-soluble carrier. The base-soluble carrier exists largely in an anionic form in at least a portion of the pH range of from about 7.2 to about 11. However, outside the selected range, such as for example, a dirr~re,.l basic pH or below and at pH 7.2, the carrier is largely 5 pro~onated and insoluble in water. Therefore, the carrier could self asse,-~L le to microspheres at a dirr~re..t basic pH or acidic or neutral pH, and the active agent in the composition would not be released until the carrier solubilizes upon encountering the selected basic pH.
Compositions which are large~ed to a neutral environment can be 10 made selectively soluble at neutral pH. These compositions are prepared with a neutral-soluble carrier. The neutral-soluble carrier exists largely in a neutral form at neutral pH, i,e. from about 6.8 to about 7.2. However, above or below this range, the carrier is insoluble in water. Therefore, the carrier could selfasse"ll)le to microspheres at acidic or basic pH, and the active agent in the 1 5 co, n~,osition would not be released until the carrier solubilizes upon encountering a neutral pH.
In a typical formulation, the final solution can contain from about 10 mg to about 2000 mg of carrier per ml of solution, preferably between about 75 to about 500 mg of carrier per ml of solution, and most preferably from 20 about 75 to about 200 mg per ml. Optionally, the mixture is heated to a temperature between about 20~ C and about 60~ C, preferably about 40~C, until the carrier dissolves. Particulates remaining in the solution may be filtered out by conventional means such as gravity filtration over filter paper. The carrier solution usually is ",ai.,tail,ed at the elevated temperature and is mixed with the 25 non-biologically active agent and a precipitator, for example, an acid solution such as, for example, aqueous acetic or citric acid at a concentration ranging from about 1 N to about 3N for acid insoluble carriers, a basic solution for base insoluble carriers, and a neul~dl;~ing solution for neutral insoluble carriers. The active agent can be mixed with the precipitating solution or can be used 30 separately. The resultant mixture is maintained for a period of time sufficient for microsphere kr",~lion as observed by light microscopy. Although it is preferred that the precipitating solution is added to the carrier solution, the carrier solution can be added to the precipitating solution as well.
CA 0221903~ 1997-11-13 WO ~ 070 PCT/US96/10183 The solutions above may optionally contain additives such as stabilizing additives. The presence of such additives promotes the stability anddispersability of the non-biologically active agent in solution. The stabilizingadditives may be employed at a concentration ranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v). Suitable, but non-limiting examples of stabilizing additives include buffer salts, gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine. The preferred stabilizing agents are gum acacia, gelatin, and methyl cellulose.
The amount of active agent that may be encapsulated by the 10 microsphere is dependent upon a number of factors which include the concentration of active agent in the microsphere or precipitator solution as well as the affinity of the active agent for the proteinoid. The conce"l-dlion of theactive agent in the final formulation also will vary depending on the required amount for treatment. When necessar~, the exact conce,-lralion can be 15 determined by, for example, reverse phase HPLC analysis.
When the present compositions are in microsphere form, the particle size of the microsphere can also aid in providing efficient delivery of the active agent. Typically, microspheres of the present invention will have a diameter of less than 10 ,um, preferably in the range of from about 0.1 ,Llm to 20 about 10 ~m, and most preferably in the range of from 0.2 I~m to about 10 ,um.
The size of the microspheres containing an active agent can be controlled by manipulating a variety of physical or chemical parameters, such as the pH, osmolarity, ionic strength of the encapsulating solution, or size of the ions insolution, and/or by the choice of the precipitator used in the microsphere 25 forming and loading process.
The compositions of the present invention may be formulated into unit forms by the addition of one or more excipient(s), diluent(s), disintegrant(s), lubricant(s), plasticizer(s), colorant(s), or carrier vehicle(s). Preferred unit forms are liquids or aerosols.
The compositions will include activity effective amounts of the active agent or can include less than such an amount if multiple applications are to be used to deliver or apply a total activity effective amount of the active agent. Unit forms are prepared by methods conventional in the art.
CA 0221903~ 1997-11-13 W O 9G/1CC70 PCT~US96/10183 The compositions of the subject invention are useful for applying non-biologically active agents to any substrates such as for example, skin, air,fixtures, carpets, hard or soft surfaces, water systems, etc., particularly in those in which pH changes. The compositions are applied by, for example, contacting 5 the composition with the substrate.
DESCRIPTION OF THE rnt~t~RED EMBODIMENTS
The following examples illustrate the invention without li-"iLdlion.
All parts are given by weight unless otherwise indicated.
ExamDle 1 - Clove Oil/Proteinoid MicrosDheres Clove oil/proteinoid microspheres were prepared by combining a mixture of 0.1% clove oil in 10% soluble proteinoid (Glu-Asp-Tyr-Phe) with an equal volume of 1.7 N citric acid and gum to prepare a microsphere of clove 15 oil/proteinoid microsphere.
Clove oil is a relatively simple mixture of products obtained from the extraction of clove. The major components in the extract are a mixture of eugenol, caryophyllene, eugenol acetate, humulene, and copaene. Their structures are shown below.
OH
~, CH3 WO 9G/l~C70 H3C ~ CH3 OAc ~Qg~a A~
H3C ~ ~ CH3 ~ ~>~
~3C
~pha-Humu~2e WO g6,~ 70 PCT/US96/10183 ~ ~/
~Z~
~4~
The percentages of each component of the oil are summarized in Table 1.
Table- 1 .
Relative l:~.",.osition of Clove Oil Determined by Gas Cl ,. ~ .,.aloyra ~h r M~s S ~ect-G..-etry Method of Eugenol trans- alpha-Analysis Eugenol Acetate Caryophyllen Humulene e Direct 88.5 3.2 7.4 0.8 Injection Head-Space* 6.9 trace 78.0 7.5 Head-Space* * 27.8 - 52.6 4.2 1 5 * 3.8% copaene is presel ,t (sample preparation: 1 ~liter clove oil in 1 .7 grams of Dl H20 ** 7.8% copaene is present (sample preparation: 1 ,uliter clove oil neat) The final concentration of eugenol in the suspension was 0.05%, which is the saturated solubility of clove oil in deionized water. The pH of thesuspension was 1.62.
A 1 mL aliquot of the suspension was transferred to three separate 20 mL crimp-top vials. Two of the three vials were adjusted to pH 4 and 7, respectively, by addition of several drops of aqueous NaOH. All the vials were then sealed and placed in a Tekmar 7000 head-space autosampler.
A 0.05% clove oil in 0.85 N citric acid and gum mixture was CA 0221903~ 1997-11-13 prepared as a control, and 1 mL was transferred to a separate head-space vial.
An additional sample was prepared by transferring the bulk amorphous material obtained from the preparation of the proteinoid to a vial containing 1 mL of 0.85 N citric acid and gum.
Each vial was individually heated for 5 minutes at 80~C., and then was pressurized to 300 psi for 3 minutes with helium. The head-space of each vial was equilibrated in a 250~ L injection loop and then transferred to an HP
5890 gc equipped with an HP 5971 MSD. The components in the vial head-space were chromatographed on an HP cross-linked 5% methylphenyl silicon 10 column. The composition of the separate peaks in the chromatograms were identified by comparing their mass spectrum with the mass spectrum of authentic samples from a Wiley database.
The following parameters were used to acquirethe chromatograms:
injectorporttemperature = 250~C, Oventemperature = 100~C for 2 minutes, 15 then 10~C/min to 150~C for 10 minutes, detector transfer line temperature =
180~C.
Results are summarized in Tables 2 and 3 below and are illustrated in Figures 1 and 2.
~ Table - 2 Pe k~Aw~o'~ Com~ the'~ ~'sp of CloveOilProteinoid Total Relative *Sample EugenolCopaeneCaryo- Humulene Area Area phyllene 25Control 1657743trace16244172 1188710 19090625 100.00 Micros~l.e.~ 892886trace 3495762 trace 4388648 22.99 pH 1.62 Microspheres 1466342trace 6042377 253367 7762086 40.66 pH 4 30Miclos~helei. 7654119trace 7906257 365303 9036979 47.34 pH 7 Bulk 173019722307118489962 1421563 21864793 114.53 SUBSTITUTE SHEET (RULE 26) ,.-... .
. .
a e ~.a- ~
Sample Relative Peak Area Total Peak Eugenol Copaene Caryophyllene ~l-ml-lPn? Area Control 8.68 0.00 85.09 6.23 100 Micl~s~h~,~c;s 10 pH 1.62 20.35 0.00 79.65 0.00 100 Mic~ h~;s pH 4 18.89 0.00 77.84 3.26 100 Microspheres pH7 8.47 0.00 87.49 4.04 100 1 5 Bulk ~mo~hous 7.91 1.02 84.56 6.50 100 Results and Di.~cl s~ion Table 2 and Figure 1 illnst~tP that the clove oiVmicrospheres (pH =
1.62) conlilined a~ x;~ e1y 23% of the amount of clove oil otherwise present in the control ~mplP.. When, the pH of the clove/oil mic,~,~he,c sample was increased to 4, the relative cnn~ ;r,n of clove oil in the miclos~hcres increased to 41 %. A similar increase in clove oil conr~ntr~ti~n was observed when the pH of the clove/oil 25 mic~h~Gs sample was adjusted to 7.
The results inrlir~te that the eugenol/microspheres behave as a pH-myli~ted delivery system for eugenol. When the pH is increased, microspheres dissolve and release the clove oil components. The data in Table 2 shows the bulk ~moTphnus m~teri~l contained most of the clove oil used to p~c the microspheres.30 This may be expected since the amorphous m~ttq.ri~l probably ,~ sellLs the majority of the p,ule~oid used in the ~ ;on of the p,~Leinoid micl~h~ l~ s.
Table 3 and Figure 2 ilhlstr~te that the relative coll,posiLion of the head-space from the buL~ amoIphous sample closely p~r~llP.l~ that from the control, but that there are subtle v~ tion.~ in the relative composition of the head-space of the clove/oil WO 9. '~CC70 PCT/US96/10183 mic~ yh~es with increasing pH. As the pH of the microsphere suspension increases, the con~ l;nn of eugenol relative to the total clove-oil composition decreases. This suggests that the eugenol may be free or weakly bound to the mic~y~ es. In cont-~t, the LyLu~hobic colllyon~ in the clove oil. i.e. c~y-,yhyllene, hllmll1PnP, 5 and cop~n~, are released from the mi~l~,s~h~,,c;s upon ~ o1lltinn Th~ rol~, eugenol makes a smaller co~ il,u~ion to the total head-space composition of the clove-oil micru~yh~,s.
EY~ample 2 - Clove Oil/Modified Hydrolyzed Vegetable Protein The method of ~Y~mp1e 1 is followed subs~ 1g modified hydrolyzed soyl~dn protein for the p,~teilloid.
All aprli~tir)n~ patents, test methn~s, and pub1i~tinn.~ mentioned are herein are hereby i~colyolaled by lc;r~ ce. Many v~ l;ollc of the present invention 15 will suggest th~m~ ves to those sl~lled in the art in light of the above de~ d di~losllre. All such mo(lifi~ ~tinn~ are within full inten~ed scope of the a~el~ded claims.
FIELD OF THE INVENTION
The present invention relates to compositions which include fragrances or flavoranls as active agents and to the delivery of such agents.
15 These compositions are in the form of proteinoid or modified hydrolyzable vegetable protein microspheres which can be adapted to release the active agent in specific pH ranges. Methods for the preparation and for the use of such compositions are also disclosed.
Pl oteil loid microspheres have been described for encapsulating pharmaceuticals for oral deliver. (Steiner, et al., U.S. Patent No. 4,925,673).
However, it has now been discovered that other specific active agents can be delivered with proteinoid microspheres.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphic illustration of the head space concentrations of clove oil at various pH's from clove oil containing proteinoid microspheres in comparison with clove oil or clove oil in combination with proteinoids that are 30 not in microsphere form.
Figure 2 is a graphic illustration of the head space concentrations of the components of clove oil at various pH's from clove oil containing ~,roteinoid microspheres in comparison with clove oil or clove oil in the presence of protei"oids that are not in microsphere form.
CA 0221903~ 1997-11-13 SUMMARY OF THE INVENTION
Compositions useful in the delivery of fragrances and flavorant active agents, and particularly vaporous fragrances and flavorants, are provided.
These compositions comprise a microsphere which comprises (a) the active agent; and (b) (i) a proteinoid, (ii) a modified hydrolyzed vegetable protei~) wherein the pro~ein is modified with an amino reactive agent, or (iii) a combination thereof.
Also contemplated is a method for preparing these compositions wherein the active agent is mixed with the proteinoid of hydrolyzed vegetable protein solution and the proteinoid or modified hydrolyzed vegetable protein is precipitated out of the solution, thereby forming a microsphere containing the active agent.
In a further embodi".ent, the active agent is applied to a substrate.
The present invention is suited to the delivery of active agents and fragrances or flavorants which optionally may be in a vaporous form either before or after incorporation into a microsphere. The present compositions incorporate readily available or easy to prepare, inexpensive starting materials.
The formulation methods of the present invention are cost effective for prepari,.g and isolating these co~-positions, are simple to perform, and are amenable to industrial scale for co"---,ercial production.
Active Agents The active agents of the present invention include flavorants and fragrances. Flavorants are compounds or compositions that either increase or enhance an existing taste or that impart a specific taste. Fragrances are compounds or compositions that either increase or enhance an existing smell or odor or that impart a specific agreeable smell or odor. These fragrances and flav~rd" l~ may be solids, liquids, vapors, or any combination thereof .
Furthermore, they may cG""~lelely or partially change state before being incor~,orated into a .-,icrosphere, while inco~l,oraled in a microsphere, or after being partially or completely released from a microsphere. Non-limiting examples CA 0221903~ 1997-11-13 WO ~ CC70 PCT/US96/10183 of fla~ orants and fragrances are clove oil.
Vaporous active agents are those that are at least partially vaporous before incorporation in a microsphere and/or while incorporated in a microsphere.
The compositions of the present invention may include one or more active agents.
Proteinoids Proteinoids are a, lificial polymers of amino acids. An amino acid 10 is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids. Amino acids suitable for use herein includenaturally occurring and synthetic amino acids as well as a- and non a-amino acids. Represe, ~talive, but not limiting, amino acids suitable for use in the present invention are generally of the formula H - N ~R1) - (R2- C) - OH
wherein: R' is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
R2 is C1-C24 alkyl, C2-C24 alkenyl, C3-C~o cycloalkyl, C3-C~o cycloalkenyl, phenyl, naphthyl, (C,-C10 alkyl) phenyl, (C2-C,O
alkenyl) phenyl, (C,-C,O alkyl) naphthyl, (C2-C,O alkenyl) naphthyl, phenyl (C,-C,O alkyl), phenyl (C2-C,O alkenyl), naphthyl (C,-C,O alkyl), or naphthyl (C2-C,O alkenyl);
R2 being optionally substituted with C~-C4 alkyl, C2-C4 alkenyl, C~-C4 alkoxy, -OH, -SH, -Co2R3, C3-C~o cycloalkyl, C3-C~o cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C~-C,O alk)aryl, ar(C,-C,O alkyl) or any combination thereof;
R2 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R3 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
The pr~rerled amino acids for use in the present invention are ~-W O ~f"CC70 PCT~US96/10183 amino acids, and most preferably are naturally occurring ~-amino acids. Many amino acids and amino acid esters are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl, USA); Sigma Chemical Co. (St. Louis, M0, USA); and Fluka Chemical Corp. (Ronkonkoma, 5 NY, USA).
Preferred naturally occurring amino acids for use in the present invention as amino acids or components of a peptide are alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, Iysine, methionine, ornithine, 10 phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxy proline, y-carboxyglul~l.,ale, phenylglycine, or 0-phosphoserine. The preferled amino acids are arginine, leucine, Iysine, phenylalanine, tyrosine, tryptophan, valine, and phenylglycine.
Non-limiting examples of non-naturally occurring amino acids for 15 use in the present invention are,6-alanine, a-amino butyric acid, y-amino butyric acid, y-(aminophenyl) butyric acid, a-amino isobutyric acid, citrulline, ~-aminocaproic acid, 7-amino heptanoic acid, ,~-aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, y-glutamic acid, cysteine, ~-lysine, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-20 nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrah~droisoquinoline-3-carboxylic acid, and thioproline.
The proteinoids useful herein preferably are prepared from mixed amino acids. Plerer~ed proteinoids are condensation polymers, and most preferably, are thermal condensation polymers. These polymers may be directed 25 or random polymers. Protei, .oids can be linear, branched, or cyclical, and certain proteinoids can be units of other linear, branched, or cyclical proteinoids.
Special mention is made of diketopiperazines. Diketopiperazines are six member ring compounds. The ring includes two nitrogen atoms and is substituted at two carbons with two oxygen atoms. Preferably, the carbonyl 30 groups are at the 1 and 4 ring positions. These rings can be optionally, and most often are, further substituted.
Diketopiperazine ring systems may be generated during thermal poly",eri~alion or condensation of amino acids or amino acid derivatives.
W 0 9GI~C070 PCTAUS96/10183 (Gyore, J; Ecet M. Proceedings Fourth ICTA ~Thermal AnalysisJ, 1974, 2, 387-394 (1974)). These six ",e,-lbered ring systems were presumably generated by intra-molecular cyclization of the dimer prior to further chain growth or directly from a linear peptide (Reddy, A.V., Int. J. Peptide Protein Res., 40, 472-476 5 (1992); Mazurov, A.A. et al., Int. J. Peptide Protein Res., 42, 14-19 (1993)).Diketopiperazines can also be formed by cyclodimerization of amino acid ester derivatives as described by Katchalski et al., J. Amer. Chem. Soc., 68, 879-880 (1946), by cyclization of dipeptide ester derivatives, or by thermaldehydration of amino acid derivatives and high boiling solvents as described by 10 Kopple et al., J. Org. Chem., 33 (2), 862-864 (1968).
Diketopiperazines typically are formed from a-amino acids.
Rlererably, the a-amino acids of which the diketopiperazines are derived are glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers of any of the foregoing.
Special mention is made of diketopiperazines of the formula R~ ~N~R6 20 wherein R4, R5, R6, and R7 independently are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (Cl-C10alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl(C1-C1O
alkenyl), naphthyl (C1-C10 alkyl), and naphthyl (C1-C10 alkenyl); any of R4, R5, R~, and R7 independently may optionally be substituted with C1-C4 alkyl, C1-C4 25 alkenyl, C1-C4 alkoxy, -OH, -SH, and -CO2R8 or any combination thereof; R8 is hydrogen, C1-C4 alkyl or C1-C4 alkenyl; and any of R4, R5, R6, and R' independently may optionally be interrupted by oxygen, nitrogen, sulfur, or any combination thereof.
The phenyl or naphthyl groups may optionally be substituted.
CA 022l903~ l997-ll-l3 Suitable, but non-limiting, examples of substituents are C1_CB alkyl, C1 C6 alkenyl, C1-C~ alkoxy, -OH, -SH, or CO2R9 wherein R9 is hydrogen, Cl-C~ alkyl, or Cl-C~ alkenyl.
Pl erer~bly, R6 and R~ independently are hydrogen, C1 -C4 alkyl or C1-C4 alkenyl. Special mention is made of diketopiperazines which are pre~er.e.l complexing pert~"ba"L~. These diketopiperazines include the unsubstituted diketopiperazine in which R4, R5, R6, and R' are hydrogen, and diketopiperazineswhich are substituted at one or both of the nitrogen atoms in the ring, i.e. mono or di-N-substituted. Special mention is made of the N-substituted 10 diketopiperazine wherein one or both of the nitrogen atoms is substituted with a methyl group.
Special mention is also made of diketopiperazines of the formula Rl~l~N~
N J~ ll H~
wherein R10 and R1' independently are hydrogen, Cl-C24 alkyl, C,-C24 alkenyl, phenyl, naphthyl, (Cl-Cl0 alkyl)phenyl, (Cl-Cl0 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl(C1-C10 alkenyl), naphthyl (Cl-C10 alkyl), and naphthyl (Cl-Cl0 alkenyl); but both Rl~ and 20 Rll can not be hydrogen; either or both R10 or R11 independently may optionally be substituted with C1-C4 alkyl, C1-C4 alkenyl, C,-C4 alkoxy, -OH, -SH, and -CO2R12 or any combination thereof; R12 is hydrogen, C1-C4 alkyl or C1-C4 alkenyl;
and either or both R10 and R11 independently may optionally be interrupted by oxygen, nitrogen, sulfur, or any combination thereof.
The phenyl or naphthyl groups may optionally be substituted.
Suitable, but non-limiting, examples of substituents are Cl-C~ alkyl, Cl-C6 alkenyl, C1-C~3 alkoxy, -OH, -SH, or CO2R13 wherein Rl3 is hydrogen, Cl-C~ alkyl, or C1-C~ alkenyl. When one of R10 or R11 is hydrogen, the diketopiperazine is mono-carbon-(C)-substituted. When neither R10 nor R1 1 is hydrogen, the CA 0221903~ 1997-11-13 W O 9f~1~C~u PCTAJS96/lû183 diketopiperazine is di-carbon-(C)-substituted.
Pleferably, R10, R1~, or both R'~ and R11, contain at least one functional group, a functional group being a non-hyd, ocarl,on portion responsible for characteristic reactions of the molecule. Simple functional groups are 5 heteroatoms including, but not limited to halogens, oxygen, sulfur, nitrogen, and the like, attached to, the carbon of an alkyl group by a single or multiple bond.
Other functional groups include, but are not limited to, for example, hydroxyl groups, carboxyl groups, amide groups, amine groups, substituted amine groups, and the like.
Preferred diketopiperazines are those which are substituted at one or two of the carbons of the ring with a functional group that includes at leastone carboxyl functionality.
Modified Hvdrolyzed Vegetable Protein Modified hydrolyzed vegetable protei-l is prepared from hydrolyzed vegetable protein. Hydrolyzed vegetable protein is a product which is derived from der~lLed vegetable meal. In practicing the present invention, acid or enzyme hydrolyzed vegetable proteins are useful. The vegetable proteins generally contain titratable carboxylic acid groups (COOH) ranging from about 20 3 to about 8 milliequivalents/g, ~., ererably from about 4 to about 6 milliequivalents/g, and total free amino groups (NH2) ranging from about 3 to about 9 milliequivalents/g, preferc,l~ly ranging from about 4 to about 7 milliequivalents/g NH2. The molecular weight of the hydrolyzed vegetable protein ranges from about 100 daltons to about 2000 Daltons, and preferably 25 from about 200 to about 500 daltons Hydrolyzed vegel~Lle proteii) is available from a variety of commercial sources, such as, for example, Ajinomoto USA, Inc. (Teaneck, NJ);
Central Soya Co., Inc. (Fort~ayne, IN); Champlain Industries, Inc. (Clifton, NJ,);
Archer Daniels Midland (Decatur, IL), A.E. Staley Company, Gunther Products 30 Division, (Decatur, IL), and additional companies listed in "Food Engineering Mastern, an annual publication of Chilton Co., Radnor, PA. A preferred hydrolyzed vegetable protein in practicing this invention is available from Ajinomoto USA under the tradename AJI-EKI. This product is an acid CA 0221903~ 1997-11-13 WO 9~1~70 PCT~US96/10183 hydrolyzed liquid soybean protein which is derived from defatted soybean meal.
Other preferred hydrolyzed soy proteins include PROFAM 781, available from Archer Daniels Midland and PTOT 1550 and MIR-A-FOAM 100 available from A.E. Staley, Gunther Products division.
If desired, a dried protein extract of the hydrolyzed vegetable protein solution may be used to prepare the modified hydrolyzed vegetable protein of the invention. The dried protein extract is preparable by extracting the hydrolyzed vegetable ~.rotei., solution with a suitable solvent, e.g., methanol, followed by evaporating the solvent extract.
The hydrolyzed vegetable protein is modified by an amine reactive agent. Typically the hydrolyzed vegetable protein is modified by acylating or sulfonating at least one free amine group, with an acylating or sulfonating agent which reacts with at least one of the free amine groups present. Suitable, but non-limiting, examples of acylating or sulrGndLi- ,9 agents useful for preparing the 15 modified hydrolyzed vegetable protein emulsifiers of the present invention include acylating and sulfonating agents having the formula:
o R14(--C--X)n or R14--SO2--X wherein R'4 is alkyl or alkenyl, preferably having from 1 to 20 carbon atoms, or aromatic preferably having from 6 to 20 carbon atoms and n is 1 or 2.
The R'4 group can be substituted or unsubstituted, The preferred substituents include C, to C4 alkyl, C, to C4 alkenyl, C, to C4 alkoxy, Co2R'5 wherein R15 is hydrogen, C, to C4 alkyl or C1 to C4 alkenyl.
I'~leferably, R'4 is methyl, ethyl, phenyl, benzyl or naphthyl. More preferably, R14 is phenyl, or acetyl. X is a leaving group. In a reaction in which the substrate molecule becomes cleaved, part of it (the part not containing the carbon) is usually called the leaving group. See Advanced Organic Chemistrv.
2d edition, Jerry March, New York: McGraw-Hill Book (1977), page 187, 30 Typical leaving groups include, but are not limited to, halogens such as chlorine, bromine and iodine.
Examples of the acylating and sulfonating agents for modifying hydrolyzed vegetable protein include, but are not limited to, acyl halides, such CA 0221903~ 1997-11-13 as, for example, acetyl chloride, propyl chloride, benzoyl chloride, phthaloyl chloride, hexahydrophthaloyl chloride, tetrahydrophthaloyl chloride, cyclohexanoyl chloride, sebacoyl chloride, hippuryl chloride and the like; sulfonyl halides, such as, for example, benzene sulfonyl chloride, acetylsulfanilyl chloride, 5 and the like; anhydrides, such as, for example, acetic anhydride, propyl anhydride, benzoic anhydride, maleic anhydride, phthalic anhydride, tetrahydrophthalic anhydride, hexahydrophthalic anhydride, hippuric anhydride and the like. The prerer-ad acylating and sulfonating agents are benzoyl chloride, benzene sulfonyl chloride, cyclohexanoyl chloride, phthalic anhydride,10 tetrahydrophthalic anhydride, and hexahydrophthalic anhydride.
The hydrolyzed vegetable protein is typically modified by first dissolving it in aqueous alkaline solution of a metal hydroxide, e.g., sodium orpotassium hydroxide, and heating at the solution to a temperature ranging from about 50~C to about 70~C, preferably from about 50~C to about 60~C, for a 15 period ranging from about 10 minutes to about 40 minutes, preferably about 15minutes. The amount of alkali employed per mmole of titratable NH2 in the hydrolyzed vegetable protein generally ranges from about 2 to about 3 mmole, and preferably from about 2.2 to about 2.5 mmole. The pH of the solution is generally maintained from about 8 to about 13, preferably ranging from about 20 9 to about 10.
Thereafter, the acylating or sulfonating agent is added to the reaction mixture. The amount of acylating or sulfonating agent in relation to the quantity of hydrolyzed vegetable protei,l employed is based on the equivalents of total free NH2 in the hydrolyzed vegetable protei,-. Thus, from about 0.3 to 25 about 1.2 equivalents of acylating or sulfonating agent are used for each molar equivalent of total NH2 groups in the hydrolyzed vegetable protein, and prefera-bly from about 0.6 to about 1.0 equivalent of acylating or sulfonating agent foreach molar equivalent of groups NH2 groups in the hydrolyzed vegetable ,urotei~).
The modified hydrolyzed vegetable protein is then recovered from the reaction - 30 mixture using standard techniques, such as, for example, precipitation withdilute acid and filtration of the precipitate. See also, PCT Publication No.
W094/14420 (July 7, 1994).
CA 022l903~ l997-ll-l3 W O 9G,~ 70 PCTAJS96/10183 Microspheres The microspheres of the present invention can generally be of a matrix form or the microcapsule form. The matrix form includes both hollow matrix spheres in which the proteinoid forms a matrix shell around a hollow 5 center, and the active agent is distributed throughout the matrix, and a solidmatrix sphere in which the proteinoid forms a circle matrix continuing in which the active agent is distributed. The .nicroc~psule form is one in which the enc~pslJlated active agent either is in a vapor solution, a solid state, or any combination thereof, with the carrier forming a shell around the enc~psl~ated 10 material. The microcapsule form is the form most often taken by the self assembly with the ~Jroteinoids of the present invention. The microspheres can also have the flavor or fragrance adsorbed thereon. The microspheres are preferably non-porous.
Microspheres can be prepared by dissolving the carrier, i.e., 15 proteinoid or modified hydrolyzed vegetable protein in an appropriate solvent and then stimulating self assembly by contacting the carrier solution with a precipitator. Solubility of the carrier can be regulated by the selection of theappropriate amino acid.
Furthermore, the carrier, and therefore, the microsphere 20 compositions of the present invention can be pH adapted to be selectively soluble in specific acidic, basic, or neutral pH ranges.
Compositions which are targeted to an acidic environment can be made selectively soluble at specific ranges of acidic pH. These compositions areprepared with an acid-soluble carrier. The acid-soluble carrier exists largely in 25 the cation form in at least a portion of the pH range from about 1 to about 6.8.
However, outside the selected range, such as for example, at a different acidic pH or above about 6.8 or at selected ranges above pH 6.8, the carrier is largelyunprotonated and insoluble in water. Therefore, the carrier could self assemble to microspheres at a different acidic pH or at a basic or neutral pH, and the 30 active agent in the composition would not be released until the carrier solubilizes upon encountering the selected acidic pH.
Compositions which are to be targeted to an alkaline environment can be made selectively soluble at specific ranges of alkaline pH. These CA 0221903~ 1997-11-13 WO 96~-C7~ PCTAJS96/10183 compositions are prepared with a base-soluble carrier. The base-soluble carrier exists largely in an anionic form in at least a portion of the pH range of from about 7.2 to about 11. However, outside the selected range, such as for example, a dirr~re,.l basic pH or below and at pH 7.2, the carrier is largely 5 pro~onated and insoluble in water. Therefore, the carrier could self asse,-~L le to microspheres at a dirr~re..t basic pH or acidic or neutral pH, and the active agent in the composition would not be released until the carrier solubilizes upon encountering the selected basic pH.
Compositions which are large~ed to a neutral environment can be 10 made selectively soluble at neutral pH. These compositions are prepared with a neutral-soluble carrier. The neutral-soluble carrier exists largely in a neutral form at neutral pH, i,e. from about 6.8 to about 7.2. However, above or below this range, the carrier is insoluble in water. Therefore, the carrier could selfasse"ll)le to microspheres at acidic or basic pH, and the active agent in the 1 5 co, n~,osition would not be released until the carrier solubilizes upon encountering a neutral pH.
In a typical formulation, the final solution can contain from about 10 mg to about 2000 mg of carrier per ml of solution, preferably between about 75 to about 500 mg of carrier per ml of solution, and most preferably from 20 about 75 to about 200 mg per ml. Optionally, the mixture is heated to a temperature between about 20~ C and about 60~ C, preferably about 40~C, until the carrier dissolves. Particulates remaining in the solution may be filtered out by conventional means such as gravity filtration over filter paper. The carrier solution usually is ",ai.,tail,ed at the elevated temperature and is mixed with the 25 non-biologically active agent and a precipitator, for example, an acid solution such as, for example, aqueous acetic or citric acid at a concentration ranging from about 1 N to about 3N for acid insoluble carriers, a basic solution for base insoluble carriers, and a neul~dl;~ing solution for neutral insoluble carriers. The active agent can be mixed with the precipitating solution or can be used 30 separately. The resultant mixture is maintained for a period of time sufficient for microsphere kr",~lion as observed by light microscopy. Although it is preferred that the precipitating solution is added to the carrier solution, the carrier solution can be added to the precipitating solution as well.
CA 0221903~ 1997-11-13 WO ~ 070 PCT/US96/10183 The solutions above may optionally contain additives such as stabilizing additives. The presence of such additives promotes the stability anddispersability of the non-biologically active agent in solution. The stabilizingadditives may be employed at a concentration ranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v). Suitable, but non-limiting examples of stabilizing additives include buffer salts, gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine. The preferred stabilizing agents are gum acacia, gelatin, and methyl cellulose.
The amount of active agent that may be encapsulated by the 10 microsphere is dependent upon a number of factors which include the concentration of active agent in the microsphere or precipitator solution as well as the affinity of the active agent for the proteinoid. The conce"l-dlion of theactive agent in the final formulation also will vary depending on the required amount for treatment. When necessar~, the exact conce,-lralion can be 15 determined by, for example, reverse phase HPLC analysis.
When the present compositions are in microsphere form, the particle size of the microsphere can also aid in providing efficient delivery of the active agent. Typically, microspheres of the present invention will have a diameter of less than 10 ,um, preferably in the range of from about 0.1 ,Llm to 20 about 10 ~m, and most preferably in the range of from 0.2 I~m to about 10 ,um.
The size of the microspheres containing an active agent can be controlled by manipulating a variety of physical or chemical parameters, such as the pH, osmolarity, ionic strength of the encapsulating solution, or size of the ions insolution, and/or by the choice of the precipitator used in the microsphere 25 forming and loading process.
The compositions of the present invention may be formulated into unit forms by the addition of one or more excipient(s), diluent(s), disintegrant(s), lubricant(s), plasticizer(s), colorant(s), or carrier vehicle(s). Preferred unit forms are liquids or aerosols.
The compositions will include activity effective amounts of the active agent or can include less than such an amount if multiple applications are to be used to deliver or apply a total activity effective amount of the active agent. Unit forms are prepared by methods conventional in the art.
CA 0221903~ 1997-11-13 W O 9G/1CC70 PCT~US96/10183 The compositions of the subject invention are useful for applying non-biologically active agents to any substrates such as for example, skin, air,fixtures, carpets, hard or soft surfaces, water systems, etc., particularly in those in which pH changes. The compositions are applied by, for example, contacting 5 the composition with the substrate.
DESCRIPTION OF THE rnt~t~RED EMBODIMENTS
The following examples illustrate the invention without li-"iLdlion.
All parts are given by weight unless otherwise indicated.
ExamDle 1 - Clove Oil/Proteinoid MicrosDheres Clove oil/proteinoid microspheres were prepared by combining a mixture of 0.1% clove oil in 10% soluble proteinoid (Glu-Asp-Tyr-Phe) with an equal volume of 1.7 N citric acid and gum to prepare a microsphere of clove 15 oil/proteinoid microsphere.
Clove oil is a relatively simple mixture of products obtained from the extraction of clove. The major components in the extract are a mixture of eugenol, caryophyllene, eugenol acetate, humulene, and copaene. Their structures are shown below.
OH
~, CH3 WO 9G/l~C70 H3C ~ CH3 OAc ~Qg~a A~
H3C ~ ~ CH3 ~ ~>~
~3C
~pha-Humu~2e WO g6,~ 70 PCT/US96/10183 ~ ~/
~Z~
~4~
The percentages of each component of the oil are summarized in Table 1.
Table- 1 .
Relative l:~.",.osition of Clove Oil Determined by Gas Cl ,. ~ .,.aloyra ~h r M~s S ~ect-G..-etry Method of Eugenol trans- alpha-Analysis Eugenol Acetate Caryophyllen Humulene e Direct 88.5 3.2 7.4 0.8 Injection Head-Space* 6.9 trace 78.0 7.5 Head-Space* * 27.8 - 52.6 4.2 1 5 * 3.8% copaene is presel ,t (sample preparation: 1 ~liter clove oil in 1 .7 grams of Dl H20 ** 7.8% copaene is present (sample preparation: 1 ,uliter clove oil neat) The final concentration of eugenol in the suspension was 0.05%, which is the saturated solubility of clove oil in deionized water. The pH of thesuspension was 1.62.
A 1 mL aliquot of the suspension was transferred to three separate 20 mL crimp-top vials. Two of the three vials were adjusted to pH 4 and 7, respectively, by addition of several drops of aqueous NaOH. All the vials were then sealed and placed in a Tekmar 7000 head-space autosampler.
A 0.05% clove oil in 0.85 N citric acid and gum mixture was CA 0221903~ 1997-11-13 prepared as a control, and 1 mL was transferred to a separate head-space vial.
An additional sample was prepared by transferring the bulk amorphous material obtained from the preparation of the proteinoid to a vial containing 1 mL of 0.85 N citric acid and gum.
Each vial was individually heated for 5 minutes at 80~C., and then was pressurized to 300 psi for 3 minutes with helium. The head-space of each vial was equilibrated in a 250~ L injection loop and then transferred to an HP
5890 gc equipped with an HP 5971 MSD. The components in the vial head-space were chromatographed on an HP cross-linked 5% methylphenyl silicon 10 column. The composition of the separate peaks in the chromatograms were identified by comparing their mass spectrum with the mass spectrum of authentic samples from a Wiley database.
The following parameters were used to acquirethe chromatograms:
injectorporttemperature = 250~C, Oventemperature = 100~C for 2 minutes, 15 then 10~C/min to 150~C for 10 minutes, detector transfer line temperature =
180~C.
Results are summarized in Tables 2 and 3 below and are illustrated in Figures 1 and 2.
~ Table - 2 Pe k~Aw~o'~ Com~ the'~ ~'sp of CloveOilProteinoid Total Relative *Sample EugenolCopaeneCaryo- Humulene Area Area phyllene 25Control 1657743trace16244172 1188710 19090625 100.00 Micros~l.e.~ 892886trace 3495762 trace 4388648 22.99 pH 1.62 Microspheres 1466342trace 6042377 253367 7762086 40.66 pH 4 30Miclos~helei. 7654119trace 7906257 365303 9036979 47.34 pH 7 Bulk 173019722307118489962 1421563 21864793 114.53 SUBSTITUTE SHEET (RULE 26) ,.-... .
. .
a e ~.a- ~
Sample Relative Peak Area Total Peak Eugenol Copaene Caryophyllene ~l-ml-lPn? Area Control 8.68 0.00 85.09 6.23 100 Micl~s~h~,~c;s 10 pH 1.62 20.35 0.00 79.65 0.00 100 Mic~ h~;s pH 4 18.89 0.00 77.84 3.26 100 Microspheres pH7 8.47 0.00 87.49 4.04 100 1 5 Bulk ~mo~hous 7.91 1.02 84.56 6.50 100 Results and Di.~cl s~ion Table 2 and Figure 1 illnst~tP that the clove oiVmicrospheres (pH =
1.62) conlilined a~ x;~ e1y 23% of the amount of clove oil otherwise present in the control ~mplP.. When, the pH of the clove/oil mic,~,~he,c sample was increased to 4, the relative cnn~ ;r,n of clove oil in the miclos~hcres increased to 41 %. A similar increase in clove oil conr~ntr~ti~n was observed when the pH of the clove/oil 25 mic~h~Gs sample was adjusted to 7.
The results inrlir~te that the eugenol/microspheres behave as a pH-myli~ted delivery system for eugenol. When the pH is increased, microspheres dissolve and release the clove oil components. The data in Table 2 shows the bulk ~moTphnus m~teri~l contained most of the clove oil used to p~c the microspheres.30 This may be expected since the amorphous m~ttq.ri~l probably ,~ sellLs the majority of the p,ule~oid used in the ~ ;on of the p,~Leinoid micl~h~ l~ s.
Table 3 and Figure 2 ilhlstr~te that the relative coll,posiLion of the head-space from the buL~ amoIphous sample closely p~r~llP.l~ that from the control, but that there are subtle v~ tion.~ in the relative composition of the head-space of the clove/oil WO 9. '~CC70 PCT/US96/10183 mic~ yh~es with increasing pH. As the pH of the microsphere suspension increases, the con~ l;nn of eugenol relative to the total clove-oil composition decreases. This suggests that the eugenol may be free or weakly bound to the mic~y~ es. In cont-~t, the LyLu~hobic colllyon~ in the clove oil. i.e. c~y-,yhyllene, hllmll1PnP, 5 and cop~n~, are released from the mi~l~,s~h~,,c;s upon ~ o1lltinn Th~ rol~, eugenol makes a smaller co~ il,u~ion to the total head-space composition of the clove-oil micru~yh~,s.
EY~ample 2 - Clove Oil/Modified Hydrolyzed Vegetable Protein The method of ~Y~mp1e 1 is followed subs~ 1g modified hydrolyzed soyl~dn protein for the p,~teilloid.
All aprli~tir)n~ patents, test methn~s, and pub1i~tinn.~ mentioned are herein are hereby i~colyolaled by lc;r~ ce. Many v~ l;ollc of the present invention 15 will suggest th~m~ ves to those sl~lled in the art in light of the above de~ d di~losllre. All such mo(lifi~ ~tinn~ are within full inten~ed scope of the a~el~ded claims.
Claims (24)
1. A composition comprising a microsphere, said microsphere comprising:
(a) an active agent comprising a member selected from the group consisting of a fragrance, a flavorant, or a combination thereof, and (b) (i) a proteinoid, (ii) a modified hydrolyzed vegetable protein wherein said protein is modified with an amine reactive agent, or (iii) a combination thereof.
(a) an active agent comprising a member selected from the group consisting of a fragrance, a flavorant, or a combination thereof, and (b) (i) a proteinoid, (ii) a modified hydrolyzed vegetable protein wherein said protein is modified with an amine reactive agent, or (iii) a combination thereof.
2. A composition as defined in claim 1, wherein said active agent comprises a perfume.
3. A composition as defined in claim 1, wherein said active agent comprises a deodorant.
4. A composition as defined in claim 1, wherein said active agent comprises a vapor.
5. A composition as defined in claim 1, wherein said proteinoid comprises mixed amino acids.
6. A composition as defined in claim 5, wherein said proteinoid comprises a polymer of mixed amino acids.
7. A composition as defined in claim 1, wherein said proteinoid comprises a condensation polymer.
8. A composition as defined in claim 7, wherein said proteinoid comprises a condensation polymer.
9. A composition as defined in claim 1, wherein said proteinoid comprises a directed polymer.
10. A composition as defined in claim 1, wherein said proteinoid comprises a random polymer.
11. A composition as defined in claim 1, wherein said proteinoid comprises a diketopiperazine.
12. A composition as defined in claim 1, wherein said hydrolyzed vegetable protein comprises acid hydrolyzed soybean protein.
13. A composition as defined in claim 1, wherein said amine reactive modifying group is selected from the group consisting of a benzene sulfonyl group, a benzoyl group, a phthaloyl group, a tetrahydrophthaloyl group, and a cyclohexanoyl group.
14. A composition as defined in claim 1, wherein said microsphere comprises a microcapsule.
15. A composition as defined in claim 14, wherein said microcapsule is non-porous.
16. A composition as defined in claim 1, wherein said composition is pH adapted.
17. A composition as defined in claim 16, wherein said composition is adapted to release said active agent at an basic pH.
18. A composition as defined in claim 16, wherein said composition is adapted to release said non-biologically active agent at an basic pH.
19. A composition as defined in claim 16, wherein said composition is adapted to release said active agent at a neutral pH.
20. A composition as defined in claim 1, wherein said microsphere has a diameter less than of 10 µm.
21. A composition comprising:
(a) a vaporous active agent, in (b) a microsphere comprising a proteinoid, a modified hydrolyzed vegetable protein, or a combination thereof.
(a) a vaporous active agent, in (b) a microsphere comprising a proteinoid, a modified hydrolyzed vegetable protein, or a combination thereof.
22. A method for applying an active agent to a substrate, said method comprising contacting said substrate with a composition as defined in claim 1.
23. A method as defined in claim 22, wherein said substrate comprises skin.
24. A method for preparing a composition as defined in claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/484,293 US5824345A (en) | 1995-06-07 | 1995-06-07 | Fragrances and flavorants |
| US08/484,293 | 1995-06-07 | ||
| US08/484,293(CON) | 1995-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2219035A1 true CA2219035A1 (en) | 1996-12-19 |
Family
ID=23923548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002219035A Abandoned CA2219035A1 (en) | 1995-06-07 | 1996-06-06 | Fragrances and flavorants |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5824345A (en) |
| EP (1) | EP0831784A4 (en) |
| JP (1) | JPH11507916A (en) |
| AU (1) | AU6276596A (en) |
| CA (1) | CA2219035A1 (en) |
| WO (1) | WO1996040070A1 (en) |
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-
1995
- 1995-06-07 US US08/484,293 patent/US5824345A/en not_active Expired - Lifetime
-
1996
- 1996-06-06 WO PCT/US1996/010183 patent/WO1996040070A1/en not_active Application Discontinuation
- 1996-06-06 JP JP9502232A patent/JPH11507916A/en active Pending
- 1996-06-06 CA CA002219035A patent/CA2219035A1/en not_active Abandoned
- 1996-06-06 EP EP96921566A patent/EP0831784A4/en not_active Withdrawn
- 1996-06-06 AU AU62765/96A patent/AU6276596A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11507916A (en) | 1999-07-13 |
| WO1996040070A1 (en) | 1996-12-19 |
| US5824345A (en) | 1998-10-20 |
| EP0831784A1 (en) | 1998-04-01 |
| EP0831784A4 (en) | 2000-07-19 |
| AU6276596A (en) | 1996-12-30 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |