CA2099093A1 - Organic envelopment - Google Patents

Organic envelopment

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Publication number
CA2099093A1
CA2099093A1 CA 2099093 CA2099093A CA2099093A1 CA 2099093 A1 CA2099093 A1 CA 2099093A1 CA 2099093 CA2099093 CA 2099093 CA 2099093 A CA2099093 A CA 2099093A CA 2099093 A1 CA2099093 A1 CA 2099093A1
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CA
Canada
Prior art keywords
organic
organic substance
phase
lipid
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2099093
Other languages
French (fr)
Inventor
John R. Lau
Blair Geho
Darryl H. Woods
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2099093A1 publication Critical patent/CA2099093A1/en
Abandoned legal-status Critical Current

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  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Cosmetics (AREA)

Abstract

ABSTRACT OF THE INVENTION

An area enhancement organic substance is carried as a burden by a lipid membrane and is substantially insoluble in water and soluble in organic solvents. The organic substance is enveloped by the lipid membrane to effect sequestration of the burden. There is also disclosed a method for preparation of the area enhancement chemical.

Description

2 ~ 3 The invention relates to organic envelopment, especially to organic envelopment of volatile organic substances by lipid membranes .

Liposomes can be formed from phospholipid molecules that are not very soluble in aqueous media but are soluble in organic solvents.

The liposomes per se have very little intrinsic usefulness, but are widely employed to carry water soluble solutes in their core volume. The phospholipid is placed in water media, and energy, such as by sonication or micro~luidization, is applied to cause the liposomes to form from the phospholipid and capture some of the solute in their core volume.

Liposomes are formed in a water environment as desrribed, because they are soluble in organic solvents, and can not be normally employed to capture and carry significant, large amounts of materials which are soluble in organic solv~nts.

The fi21d of the invention, therefore, is in the discovery that pseudo core volumes can be formed in liposomes to develop the same advantages for organic materials as hereto~ore available for water solute.

To illustrate the timeliness o~ this invention~ one state in the U.S.A. has now passed reyulations concerning the amount of volatile substances which may be used in products, and many other states are actively consi~ring such legislation. It is undPrstood that other countri2s throughout the world are considering such legislation.

The law as it now exists in Cali~ornia, U.S.A. states that no existing product may be re~ormulated to încrease :,' 2~0~3 either the products total HVOC (High Volatility Oryanic Compound] content or total ethanol content. An existing product may b~ reformulated to reduce the products total ethanol content or total HVOC content, as long as the formulation does not increase the products total HVOC
content.

Liposomes are known to encapsulate water soluble pharmacological agents in their core volume. Thus, these ~
agents are subdivided into small groups of molecules ~ ~-~eparated from the surrounding media and other vesicle entities. The liposomes have potential for site specific delivery and for their use as carriers to enhance ~;
therapeutic and protective indices. ~
~ . -The prior art method of making liposomes is to subject a mixture o~ an amphiphatic phospholipid, such as lecithin,and an aqueous solution of the intended burden, to high energy output, such as sonication or microfluidization. The a~phiphatic lipid breaks into smaller units which then form bladders known as liposomes. In the process, some of the ~-aqueous media is captured in the core volume of the liposomes.

This basic known system, as described, is sati~Eactory for aqueous solvents because both inner and outer surfaces of the bladder are hydrophilic, ~ut is considered inoperative for organic m~lecules that are minimally soluble in aqueous media.

This invention distinguishes over all known prior art, including intensive litsrature studies. The discovery is that formation of amphiphatic lipids into liposomes in the pre6ence of organic molecules that are minimally soluble in aqueous media, exhibit a phenomenon of sequestration by f~
lamellar liposomal en~rapment of the organic substance. The organic substance would not ordinarily be expected to fill the aqueous core volume of a liposome during formation. The outermost portion of the bipolar lipid membrane, both on the exterior surface and on the core volume wall, is a hydrophilic sphere. Therefore, it is generally accepted as fact that an organic substance would not be encapsulated.

It is an object of this invention to provide a delivery system ~or chemicals which are soluble in an organic solvent, but not water soluble, by capture of such chemicals in a bipolar lipid liposome. This object may be achieved by lamellar envelopment~

Although this invention resides in the generic discovsry that organic solvent type substances can be carried as a burden by a vesicle, an anchor molecular may be provided to anchor the liposome to a target organ, such as the epidermis. See prior U.S. Patent Serial No. 07/726,037, which is now issued as U.S. Patent No. 5,173,303.

According to the invention there is provided a liquid organic substance which is volatile at ambient temperature and pressure, said substance being substantially insoluble in water and highly soluble in organic solvents, captured by lipid lamellarly envelopment resulting in sequestration in a bipolar lipid membrane.

Also according to the invention there is provicled an area enhancement agent which is substantially insoluble in water and soluble in organic solvents; the agent having a ~irst phas~ which is a liposome lamellae enveloping a second phase which is a bio-organic substance soluble in organic solvents and substantially insoluble in water~

.

9 ~
Also according to the invention there is provided a method of preparation of an area enhancement organic ~ :
substances which is volatile at ambient temperature and pressure, carried as a burden by a lipid membrane, said membrane and burden being composed of a first phase which is an amphiphatic lipid, a second phase which is water, and a ~:~
third phase which is a liquid organic substance selected from the class consisting of aromatic organic materials, wherein the method comprises the steps of~
first producing multilamellar membrane structures by mixing said first and second phases and processing by energy input to produce multilamellar membrane structures, and;
thereafter, combirling the organic phase with the resulting membrane structures and agitating the membrane 5 structures and third phase;
whereby, the membrane structures, when brought into contact with a particles of lipid organic substance, will react to engulf the organic substance, thereby affecting sequestration of the burden.

The term "burden" as used harein, shall refer in general to a swbstantially water insoluble, biologically active, aromatic organic hydrocarbon derivative which may be used with or without anchor or target molecules to keep the liposome in a selected environment or to cause the combination o~ a target molecule and a liposome to travel to a designated target area. It may be, ~or example, a room freshener chemical which is usually an organic material not considered a candidate ~or serving as a burden in a liposome. However, it can also be an enhanc~ment chemical, and an insect repellant, or a cosmeti~ such as per~ume~
Water in soluble sunscreens ~it the description.

2~9909~
,~

The burden is sequestered by lamellar envelopment in a bipolar lipid liposome in the special sense of this invention.

Lipo~omes cannot be formed in an organic solvent, and water insoluble chemicals cannot be trapped in an aqueous core volume of a liposome.

This invention involves the phenomenon of physically sequestering liquid organic substances, which are volatile at ambient temperature and pressure, by lamellar envelopment. It is to be distinguished from microdroplets o~ water insoluble drugs coa~ed with a phospholipid prepared by sonication.

To understand this invention, it is well to understand what it is not. It is not entrapment within a lipid vesicle aqueous core volume as is now well known in the art, nor a coating of polar lipid on microdroplets.

In the envelopment phenomenon of the invention, phospholipid lamellar membrane functions as the enveloper or as a wrapper of sequestered burden.

The invention will be described by way o~ example with re~erence to the drawing, in which Fiqure l is a sketch based on electron micrographs illustra-ting a process of an organic particle being enveloped and 6equestered as if wrapped by a liposomal lamellar structure.

Because the invention is a unique means for dispensing a biologically active substance, and is not in the substance per se, re~?erence hereinafter ~?or disclosure will generally include any burden which is insoluble in water and soluble in organic solvent, and is volatile at ambient temperature `.: ~ ~ .. ' ' '- "'' ' '; ` ' ' ~ 2~9~:3 ~

and pressure. Normally such substance can not be formed and sequestered by a liposome. Examples include, but are not limited to, perfume and organic air freshener substances.
Sunscreens are Pxamples of substances which can be used to prevent sunburn.

The term l'envelop" or "wrap" resulting in sequestration by liposomal lamellae is a concise statement of the engul~ment pheno~enon and excludes the usual entrapment of organics within the bilayer itself. To engulf is to swallow up. This invention is due to the discovery that a water insoluble substance can be env~loped, wrapped, or engulfed by a lamellar lipid in what has heretofore been considered a hostile environment.

"Encapsulate", as used herein, i6 limited to a very specific meaning which is fully developed in the disclosur~
of the document. The term excludes core volume entrapment.

"Bio-organic" and "biologically active" and 'laromatic hydrocar~on" shall refer to an organic substance, practically insoluble in water and shall include those organic medications useful for treating skin for relief? of pain, as well as to organic substances suitable for distribution in the volume of a space. ~or example, such organic substances may be misted or otherwise distributed in a space such as a room. Another utility is enhancement chemicals such as per~umes and sunscreens which may be used on the skin or, in the case of perfumes, sprayed into a space as a room freshener or other area enhancement agents.
.

This invention provides, for example, an article of manufacture for release of a fragrancP oil as an air freshener. The fragrance oil, such as citrus oil or cinnamon oil, is enveloped within a bipolar lipid body.

.
'`

. ~ ~

: ~:?~ . , : , ' : : . -: '~ '. , . ' ' ` '~' ' , 2 ~ 3 An exemplary procedure used for making a commercial product as tested is set forth below:
1. 120 g of hydroxylated lecithin is put into an 800 mL beaker. 525 g of deionized water is added to the beaker. The sample was slowly polytroned with an ultra-Turrax TP-18/1051 Polytron from Janke and Kunkel IKA Laboratory, at setting #~, for 15 minutes.

2. After the hydroxylated lecithin and water is mixed, 180 g of 100% citrus oil is added to the 645 g of hydroxylated lecithin solution in three aliquots of 60 g each, 5 minutes apart. After the last aliquot, the total weigh~ of 825 g i~ allowed to mix while polytroning on settiny #4 for lO minutes. Then 495 g of deionized water i5 a~deA and allowed to mix while polytroning on setting #4 for 30 minutes. The total weight of the solution at this point will be 1,320 g.

3. The 1,320 g of the citrus oil-hydroxylated lecithin suspension is processed through ~he microfluidizer a~ a head pressure of 20 psig and a sheer pressure of 2,500 psig. The total recoverable `
amount of the 1,3~0 g is recycled thre~ times through the microfluidizer under the above conditions. The initial starting temperature of the suspension should ~e about 20 degrees C, and the final temperature following microfluidization about 63 degrees C.

The citrus oil molecule is enveloped by a large multi-lamellar liposome. The capture and sequestration of the citrus oil molecule is illustrated in the five-skep illustrakion in the drawiny. In Figure 1 J the ~mall black spot 10 represents a particle of citrus oil, and the mu]kilamellar rings 12 repres4nk a liposome.

The liposome, no longer being intact, is simply a large multilamellar array of a lipid which seeks to repair itself thermodynamically, and in doing so, sequesters by lamellar envelopment the citrus oil particle or molecule by surrounding the citrus oil with the large multilamellar array o~ preformed bipolar phospholipid membrane. The citrus oil particle thus has been sequestered and protected by the liquid.

The liposomal membrane with the sequestered citrus oil will have the following propertieso it breaks upon freezing and warming, causing ~he citrus oil to coalesce into a larger separated phase. The liposomal lamellae are acting as an enveloping agent. The major portion of the lamellae evidence a distorted nonspherical pattern, as illustrated in the drawing.

The described liposomal system captures or sequesters fragrance oil in a new way. It has been shown that once the fragrance oil has been sequestered by the lamellae, its escape into the atmosphere is restricted and slowed. This concept forms the basi~ for timed release o~ ~ater insolubl2 substances such as fragrance oils and prolonys their duration of action.

It has been found that the room freshener example 9~
utility ~or the above described fragrant oil i~ preferably distributed in commercial and large volume areas by m~ans of available dispensers employing forced air through a body of such room freshener material to slowly and uniformly distribute the product throughout the atmosphere.

In home use, or smaller volume room areas, simply expo~ing the product to the atmosphere, such a~ taking a lid o~f a container thereof, will allow normal air movement to ~,. - ,., -. , -:,, .

~: : . -- .. , ., .. :,: . :

~ 2~99~3 g carry the product from the container throughout the atmosphere of the roomO

To enhance the usefulness of the article, an anchor molecule may be employed. The molecule sodium pyridinethione has a moiety that is lipophilic and a moiety that has an affinity for stratum corneum. After forming the sequestered structure, the anchor is simply mixed with the quantity of ths structure and thereafter a quantity of the final mix, when applied to the skin of a host, will attach to the dead skin cells and anchor the article to the skin.

Claims (8)

1. A liquid organic substance which is volatile at ambient temperature and pressure, said substance being substantially insoluble in water and highly soluble in organic solvents, captured by lipid lamellarly envelopment resulting in sequestration in a bipolar lipid membrane.
2. A liquid organic substance as claimed in claim 1 which is a skin treatment agent.
3. A liquid organic substance as claimed in claim 2 which is a medication.
4. A liquid organic substance as claimed in claim 2 which is a perfume.
5. An area enhancement agent which is substantially insoluble in water and soluble in organic solvents; the agent having a first phase which is a liposome lamellae enveloping a second phase which is a bio-organic substance soluble in organic solvents and substantially insoluble in water.
6. An area enhancement agent as claimed in claim 5 which is an air freshener.
7. An are enhancement agent as claimed in claim 6 in which the bio-organic substance is a fragrance oil.
8. A method of preparation of an area enhancement organic substances which is volatile at ambient temperature and pressure, carried as a burden by a lipid membrane, said membrane and burden being composed of a first phase which is an amphiphatic lipid, a second phase which is water, and a third phase which is a liquid organic substance selected from the class consisting of aromatic organic materials, wherein the method comprises the steps of:
first producing multilamellar membrane structures by mixing said first and second phases and processing by energy input to produce multilamellar membrane structures, and;
thereafter, combining the organic phase with the resulting membrane structures and agitating the membrane structures and third phase;
whereby, the membrane structures, when brought into contact with a particles of lipid organic substance, will react to engulf the organic substance, thereby affecting sequestration of the burden.
CA 2099093 1992-12-18 1993-06-23 Organic envelopment Abandoned CA2099093A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93372792A 1992-12-18 1992-12-18
US07/933,727 1992-12-18

Publications (1)

Publication Number Publication Date
CA2099093A1 true CA2099093A1 (en) 1994-06-19

Family

ID=25464415

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2099093 Abandoned CA2099093A1 (en) 1992-12-18 1993-06-23 Organic envelopment

Country Status (1)

Country Link
CA (1) CA2099093A1 (en)

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