阅读说明：本技术 用于产生合成角鲨烷和角鲨烷衍生物的方法 (Process for producing synthetic squalane and squalane derivatives ) 是由 钱德拉谢卡尔·乔西 李善和 兹米特里·马列维奇 于 2020-04-30 设计创作，主要内容包括：本申请提供了一种用于合成角鲨烷和角鲨烷衍生物作为从天然产物中提取的角鲨烯的替代品的方法。特别地,本申请提供了一种用于产生化妆品、个人护理或药物组合物的方法,所述方法包括以下步骤：(a)将Cn-脂肪酸和Cm-脂肪酸与溶剂组合以形成电解反应混合物,其中n+m之和是32；以及对所述电解反应混合物进行科尔伯电解；(b)使步骤(a)的产物进行加氢异构化反应以产生C30饱和支链烃或C30饱和支链烃的混合物；以及(c)用一种或多种成分配制所述C30饱和支链烃以产生所述化妆品、个人护理或药物组合物。还提供了包括通过此方法产生的角鲨烷和/或角鲨烷衍生物的化妆品、个人护理或药物组合物。(The present application provides a process for the synthesis of squalane and squalane derivatives as a substitute for squalene extracted from natural products. In particular, the present application provides a method for producing a cosmetic, personal care or pharmaceutical composition comprising the steps of: (a) combining a Cn-fatty acid and Cm-fatty acid with a solvent to form an electrolysis reaction mixture, wherein the sum of n + m is 32; and subjecting the electrolysis reaction mixture to a Kolbe electrolysis; (b) subjecting the product of step (a) to a hydroisomerization reaction to produce a mixture of C30 saturated, branched-chain hydrocarbons or C30 saturated, branched-chain hydrocarbons; and (C) formulating the C30 saturated, branched-chain hydrocarbon with one or more ingredients to produce the cosmetic, personal care, or pharmaceutical composition. Also provided are cosmetic, personal care or pharmaceutical compositions comprising squalane and/or squalane derivatives produced by this process.)

1. A method for producing a cosmetic, personal care or pharmaceutical composition comprising the steps of:

(a) c is to be_n-fatty acids and C_m-fatty acids are combined with a solvent to form an electrolytic reaction mixture, wherein the sum of n + m is 32; and subjecting the electrolysis reaction mixture to a Kolbe electrolysis;

(b) subjecting the product of step (a) to a hydroisomerization reaction to produce a mixture of C30 saturated, branched-chain hydrocarbons or C30 saturated, branched-chain hydrocarbons; and

(c) formulating the C30 saturated branched chain hydrocarbon with one or more ingredients to produce the cosmetic, personal care, or pharmaceutical composition.

2. The method of claim 1Wherein, said C_n-fatty acids and C_mBoth fatty acids are C16 fatty acids.

3. The method of claim 1, wherein C is_n-the fatty acid is a C8 fatty acid and said C_m-the fatty acid is a C24 fatty acid, said C_n-the fatty acid is a C9 fatty acid and said C_m-the fatty acid is a C23 fatty acid, said C_n-the fatty acid is a C10 fatty acid and said C_m-the fatty acid is a C22 fatty acid, said C_n-the fatty acid is a C11 fatty acid and said C_m-the fatty acid is a C21 fatty acid, said C_n-the fatty acid is a C12 fatty acid and said C_m-the fatty acid is a C20 fatty acid, said C_n-the fatty acid is a C13 fatty acid and said C_m-the fatty acid is a C19 fatty acid, said C_n-the fatty acid is a C14 fatty acid and said C_m-the fatty acid is a C18 fatty acid, or said C_n-the fatty acid is a C15 fatty acid and said C_m-the fatty acid is a C17 fatty acid.

4. The process according to claim 1 or 2, wherein in step (a), 1-25 mol% of the fatty acids are neutralized with a base.

5. The method of any one of claims 1 to 4, wherein step (a) is at about 10 to about 1000mA/cm²And at a temperature of from about 0 ℃ to about 80 ℃.

6. The process according to any one of claims 1 to 5, wherein the hydroisomerization of step (b) is carried out in the presence of hydrogen and a catalyst.

7. The process of claim 7, wherein the catalyst is a silica/alumina-based zeolite comprising impregnated platinum.

8. The process of any one of claims 1 to 7, wherein the hydroisomerization reaction temperature is between about 275 ℃ and about 400 ℃.

9. The process of any one of claims 1 to 8, wherein the hydroisomerization reaction pressure is between about 10 bar and about 100 bar.

10. The process of any one of claims 1 to 9, wherein the hydrogen to hydrocarbon ratio in the hydroisomerization reaction is from about 400 to about 1000.

11. A cosmetic, personal care or pharmaceutical composition produced by the method of any one of claims 1 to 10.

Technical Field

The present application relates to the field of processes for the synthesis of long chain hydrocarbons. More particularly, the present application relates to processes for synthesizing long-chain hydrocarbons for use in cosmetic and pharmaceutical formulations and formulations made thereby.

Background

Squalane is a high-end moisturizer commonly found in personal care products, especially cosmetics. Squalane acts as a lubricant in the manufacture of skin care products and when incorporated into skin care products it helps to provide a smooth and soft appearance to the skin. Squalane is also used in hair conditioning products. In addition to personal care products, squalane is also used in the manufacture of vaccines.

Squalane has the molecular formula C₃₀H₆₂And has a chemical structure shown below.

Commercially available squalane is extracted from olive oil or shark liver, or it is synthesized from sugar cane. To produce about one ton of squalane, approximately 3,000 shark livers are used. Given the current global annual demand for approximately 2,500 tons of squalane, this means that approximately 600 million deep water sharks are killed annually. Several species of sharks for squalane production are on the verge of extinction, and therefore sea-hunting sharks are banned in much of the world today. In addition, companies such as Unilihua (Unilever) and Irelay (L' Oreal) have announced that they will no longer purchase shark liver squalane for their cosmetic products, but instead utilize squalane from plant-based sources. Since shark liver has been the second largest source of squalane (second only to olive oil), these changes result in a significant reduction in the supply of squalane.

Squalane based on olive oil was the leading part of the squalane market in 2015. Squalane based on olive oil is made by hydrogenation of squalene extracted from olive oil. Considering the composition, the olive oil from the first extraction holds between about 400mg and 450mg squalene per 100g, whereas the refined olive oil contains about 25% less. Olive oil of optimal quality may contain squalene at a concentration of approximately 700mg per 100 g.

To address the global demand for squalane from olive oil, 500-. Recently, however, the xylella fastidiosa bacteria have destroyed italian olive oil production, and there is no known treatment other than destroying diseased trees. The genus Xylella (Xylella) has recently spread to the even larger spanish olive industry and threatens greek grooves (greenk grooves), resulting in an overall reduction in global olive oil production. This makes squalane more difficult to obtain from olive oil and cheaper alternatives are being sought.

An example of an alternative process is being performed by amiris (Amyris) which produces squalane by dimerization/hydrogenation of farnesene, a molecule derived from sucrose (cane sugar).

Commercial use of squalane is limited by price fluctuations due to inconsistent supply.

There remains a need for a cost-effective alternative for producing squalane that does not rely on the use of shark liver or olive oil.

The above information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. Nothing herein is to be construed as an admission that any of the foregoing information constitutes prior art against the present invention.

Disclosure of Invention

The object of the present application is to provide a process for the synthesis of squalane and squalane derivatives. According to an aspect of the present application, there is provided a method for producing a cosmetic, personal care or pharmaceutical composition, the method comprising the steps of: (a) c is to be_n-fatty acids and C_m-fatty acids are combined with a solvent to form an electrolytic reaction mixture, wherein the sum of n + m is 32; and subjecting the electrolysis reaction mixture to Kolbe electrolysis; (b) subjecting the product of step (a) to a hydroisomerization reaction to produce a mixture of C30 saturated, branched-chain hydrocarbons or C30 saturated, branched-chain hydrocarbons; and (C) formulating the C30 saturated, branched-chain hydrocarbon with one or more ingredients to produce the cosmetic, personal care, or pharmaceutical composition.

According to another aspect, there is provided a cosmetic, personal care or pharmaceutical composition produced by a process for producing a cosmetic, personal care or pharmaceutical composition, the process comprising the steps of: (a) c is to be_n-fatty acids and C_m-fatty acids are combined with a solvent to form an electrolytic reaction mixture, wherein the sum of n + m is 32; and subjecting the electrolysis reaction mixture to a Kolbe electrolysis; (b) subjecting the product of step (a) to a hydroisomerization reaction to produce a mixture of C30 saturated, branched-chain hydrocarbons or C30 saturated, branched-chain hydrocarbons; and (C) formulating the C30 saturated, branched-chain hydrocarbon with one or more ingredients to produce the cosmetic, personal care, or pharmaceutical composition.

Drawings

For a better understanding of the application as described herein, together with other aspects and further features thereof, reference is made to the following description which is to be used in conjunction with the accompanying drawings, wherein:

FIG. 1 depicts overlapping gas chromatograms of a C30 alkane blend (produced from palm fatty acids only), a C30-C34 blend (heavier emollients produced from a combination of palm and stearin fatty acids), and commercially available olive squalane; and

fig. 2 depicts a spider-web plot (spider diagram) summarizing the results of the sensory characteristics test.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in the specification and in the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The term "comprising" as used herein will be understood to mean that the following list is non-exhaustive and may or may not include any other additional suitable items, such as one or more additional features, components and/or ingredients, as the case may be.

The present inventors have found that squalane, squalane derivatives and mixtures thereof can be produced using a process comprising a kerber electrolysis step followed by a hydroisomerisation step. As used herein, the term "squalane derivative" refers to a C30 branched alkane. The squalane or squalane derivative or combination thereof is then formulated into a cosmetic, personal care or pharmaceutical product.

The process of the present application comprises decarboxylating dimerization of two fatty acids by kolbe electrolysis to form a C30 hydrocarbon, which is an alkane or alkene. The C30 hydrocarbons are then subjected to a hydroisomerization step to produce saturated and branched C30 hydrocarbons.

In one example, where C16 (palm) fatty acid is used as the starting material, a pure C30 alkane (triacontane) stream is produced. Subsequent hydroisomerization of C30 alkanes produces branched saturated hydrocarbons, such as squalane. Although not exactly the stereochemical conformation as squalane, the sensory experience of the product will be similar. Palm fatty acids can be readily purchased from oleochemical suppliers.

Kolbe electrolysis

The Kolbe electrolysis reaction (H.Kolbe, Liebigs Ann.Chem.1849,69,257-294) is a chemical reaction process for decarboxylating carboxylic acids in the process of producing hydrocarbons. The reaction can be used to electrochemically oxidize a carboxylic acid to produce an alkane, an alkene, an alkane-containing product, an alkene-containing product (i.e., comprising an alkane and an alkene, respectively)Such as substituted alkanes and substituted alkenes produced by a keerb electrolysis reaction) and mixtures thereof. The reaction proceeds through radical intermediates to produce dimerized products based on these radicals, such that C_nAcid will react with C_m-the acids combine to form alkanes and/or alkenes comprising m + n-2 carbons together with two carbon dioxide molecules and one hydrogen molecule. The free radical intermediates can also lead to shorter alkane and/or alkene products by disproportionation. In the Kolbe electrolysis, only the carboxyl groups participate in the reaction and any unsaturation that may be present in the fatty acid chain remains in the reaction product.

The Colerb electrolysis process may use a single carboxylic acid (in this case, C)_n-fatty acids and C_mThe fatty acids being identical) or mixtures of carboxylic acids (in this case, C_n-fatty acids and C_mThe fatty acids are different from each other). When a mixture of carboxylic acids is used, the mixture comprises C_n-fatty acids and C_m-fatty acids, wherein the sum of n + m is 32.

In one embodiment of the method of the present application, the kolbe electrolysis step comprises: c is to be_n-fatty acids and C_m-fatty acids are combined with a solvent to form an electrolytic reaction mixture, wherein the sum of n + m is 32; and subjecting the electrolysis reaction mixture to Kelbe electrolysis.

The fatty acids useful in the methods of the present application can be saturated (i.e., not containing any double bonds) or unsaturated (i.e., containing one or more alkenyl functional groups along the fatty acid chain). Common examples of suitable saturated fatty acids are:

-butyric acid (butyric acid): CH (CH)₃(CH₂)₂COOH or C4: 0;

-caproic acid (caproic acid): CH (CH)₃(CH₂)₄COOH or C6: 0;

-caprylic acid (caprylic acid): CH (CH)₃(CH₂)₆COOH or C8: 0;

-capric acid (decanoic acid): CH (CH)₃(CH₂)₈COOH or C10: 0;

-lauric acid (dodecanoic acid): CH (CH)₃(CH₂)₁₀COOH or C12: 0;

-myristic acid (myristic acid): CH (CH)₃(CH₂)₁₂COOH or C14: 0;

palmitic acid (hexadecanoic acid): CH (CH)₃(CH₂)₁₄COOH or C16: 0;

-stearic acid (octadecanoic acid): CH (CH)₃(CH₂)₁₆COOH or C18: 0;

-arachidic acid (eicosanoic acid): CH (CH)₃(CH₂)₁₈COOH or C20: 0; and

-behenic acid (behenic acid): CH (CH)₃(CH₂)₂₀COOH or C22: 0.

Common examples of suitable unsaturated fatty acids are:

-oleic acid: CH (CH)₃(CH₂)₇CH＝CH(CH₂)₇COOH or cis-delta⁹C18:1

-linoleic acid: CH (CH)₃(CH₂)₄CH＝CHCH₂CH＝CH(CH₂)₇COOH or C18:2

-alpha-linolenic acid: CH (CH)₃CH₂CH＝CHCH₂CH＝CHCH2CH＝CH(CH₂)₇COOH or C18:3

Arachidonic acid CH₃(CH₂)₄CH＝CHCH₂CH＝CHCH₂CH＝CHCH₂CH＝CH(CH₂)₃COOH or C20:4

Eicosapentaenoic acid or C20:5

Docosahexaenoic acid or C22:6

-sinapic acid: CH (CH)₃(CH₂)₇CH＝CH(CH₂)₁₁COOH or C22:1

As used herein, the nomenclature "Cx: y" is used to define fatty acids in terms of the number of carbon atoms in the fatty acid; where x is the number of carbon atoms in the fatty acid chain and y is the number of double bonds. When y is 0, the fatty acid is a saturated fatty acid. The term "Cx" is used herein to refer to both saturated and unsaturated fatty acids having x carbon atoms in the fatty acid chain.

By way of non-limiting example, the coler electrolysis can be carried out using: a mixture of: c4 fatty acids and C28 fatty acids, C5 fatty acids and C27 fatty acids, C6 fatty acids and C26 fatty acids, C7 fatty acids and C25 fatty acids, C8 fatty acids and C24 fatty acids, C9 fatty acids and C23 fatty acids, C10 fatty acids and C22 fatty acids, or mixtures of the following: c11 fatty acids and C21 fatty acids, C12 fatty acids and C20 fatty acids, C13 fatty acids and C19 fatty acids, C14 fatty acids and C18 fatty acids, or C15 fatty acids and C17 fatty acids. These fatty acids may be saturated or unsaturated, or any combination thereof.

In another embodiment of the process of the present application, the coler electrolysis is carried out using a C16 fatty acid. The C16 fatty acid may be a saturated or unsaturated fatty acid, or it may be a mixture of C16 fatty acids.

The fatty acids from any of the feedstocks are distilled so that the desired fatty acids are extracted from the other fatty acids present in the feedstock. For example, palm and palm olein are good sources for high yields of C16 fatty acid. However, C16 from other feedstock materials may also be used. The major product of the coler electrolysis of C16 is the C30 molecule.

Important renewable sources of fatty acids result from the hydrolysis of triglycerides of vegetable oils and animal fats.

Nominal compositions of fatty acids from various vegetable oils and animal fats are given in table 1.

Fatty acids useful for coler's primary electrolysis can also be produced by triglyceride hydrolysis, such as acid or base or enzyme catalyzed hydrolysis. The products of the hydrolysis reaction that may be present in the keerberg electrolysis reaction solution may include some unreacted triglycerides, diglycerides, monoglycerides or glycerol, depending on the starting material. In the present invention, it is preferred that the hydrolysis reaction comprises a significant aqueous phase and is designed such that all of the starting fats and oils are hydrolyzed into a water insoluble free fatty acid phase that floats on top of the aqueous phase. Preferably the glycerol by-product of the hydrolysis reaction is completely dissolved into the aqueous phase. For the kolbe electrolysis reaction, it may be advantageous to retain or recover the solvent and/or base from the hydrolysis reaction.

Suitable solvents for Kolbe electrolysis include, for example, C1-C3 alcohols. For example, the solvent employed in the Kolbe electrolysis reaction is methanol or ethanol or a mixture of C1-C3 alcohols. The cobber electrolysis reaction is tolerant to the presence of water, and water may be present in the reaction in an amount up to 40% by volume. In certain embodiments, the solubility of the reaction components and the conductivity of the electrolytic solution may be improved in a solvent system comprising a mixture of alcohol and water. Thus, in some embodiments, the solvent comprises water (e.g., water in ethanol) in an amount of about 2% to about 50%, about 5% to about 45%, about 10% to about 40%, or about 20% to about 30% by volume.

The initial reaction mixture for the Colerb electrolysis reaction may not be a solution (where the starting materials and other components are dissolved) at ambient temperature (22 ℃). During the keerb electrolysis reaction, the neutralized (i.e., salt) form of the fatty acid must be in solution. The free fatty acids may be present as a separate phase. When the carboxylate ion form of the fatty acid is converted to a hydrocarbon during electrolysis, the base formed in this reaction reacts with the free fatty acid to form a salt, thereby drawing more fatty acid (in its salt form) into solution. This continues until all the fatty acids are consumed. In one embodiment, fatty acids are continuously supplied to the reaction and hydrocarbon products are continuously removed, which helps to maintain a constant reaction rate and conduct the kolbe electrolysis in steady state mode.

In some embodiments of the invention, the colebert electrolysis may be performed at a temperature below or above room temperature. The Kolbe electrolysis reaction is carried out at a temperature in the range of from about 0 ℃ to about 100 ℃, or from about 0 ℃ to about 80 ℃, or from about 15 ℃ to about 80 ℃. Higher than atmospheric pressure may be used to prevent solvent loss or boiling over of the reaction mixture.

In the kolbe electrolysis reaction, a base may be added to convert the carboxylic acid group portion of the fatty acid to a carboxylic acid salt before the kolbe reaction begins to undergo electrolysis or during the kolbe reaction undergoing electrolysis. In some embodiments, the fatty acid will be neutralized in a range of about 1% to 80%, 1% to 60%, or 1% to 25%. In this case, percent means the concentration of neutralized fatty acid in molar units relative to the total carboxylic acid molar concentration. Suitable bases for neutralizing fatty acids are hydroxides, alkoxides or carbonates of sodium or potassium. Amine bases may also be used.

In some embodiments, an electrolyte may be added to the keerbet reaction mixture to increase the keerbet reaction mixture conductivity. Suitably, the electrolyte for improving the conductivity of the keerb reaction mixture may be selected from the group consisting of: sodium or tetraalkylammonium perchlorate, p-toluenesulfonate or tetrafluoroborate or mixtures thereof. Anions other than those from these electrolytes or other than the carboxylate of the substrate carboxylic acid may interfere and should not be present. The increase in conductivity of the mixture is consistent with a decrease in resistivity of the mixture.

The material of the cathode in the Kolbe electrolysis is typically stainless steel, nickel or graphite, but other suitable materials, including platinum or gold, may be used. The material of the anode is typically platinum, at least at the reaction surface of the anode. The anode may be a foil or plate composed of the anode material, or the anode material may be plated or fixed on a support material such as titanium, niobium, graphite or glass, with the preferred support material being titanium or niobium. For example, an anode consisting of a 1 mm-thick titanium plate plated with 1 micron of platinum may be used in a Kolbe electrolysis to give a productivity value approximately equal to that found using a platinum foil anode. Other materials may also be used as the anode, including non-porous graphite, gold, or palladium.

The current density applied to the Kolbe electrolysis, defined as the current supplied to the electrodes divided by the effective surface area of the electrodes, may be in the range of about 10 to about 1000mA/cm²Within the range of (1).

In some embodiments of the invention, when the unsaturated fatty acid is part of a fatty acid mixture, acetic acid is added to reduce the passivation voltage in the coler electrolysis, for example, as described in international PCT application WO 2016/0080335. The amount of acetic acid is between about 0.2% to about 20% by weight of the total carboxylic acids.

The hydrocarbon product of the coler electrolysis can be separated from the reaction mixture using a reaction product separator, wherein the reaction product separator is any device that can separate a liquid or solid reaction product from a liquid solution. Examples of reaction product separators include, but are not limited to, centrifugal separators, cyclones, gravity-driven separators, settling tanks, filtration systems, and distillation systems.

Hydroisomerization

The next step in the process is the hydroisomerization of the C30 hydrocarbon product of the coler electrolysis reaction to modify the character of the hydrocarbons, making it more suitable for use in cosmetic, personal care or pharmaceutical compositions.

The hydroisomerization reaction is carried out in the presence of hydrogen and a catalyst having a metal component that catalyzes the skeletal isomerization, resulting in saturated, branched hydrocarbons having the same molecular weight as the starting C30 hydrocarbon product of the kerber electrolysis step. The resulting hydrocarbon material is more stable to oxidation and more mobile at lower temperatures, which is a desirable characteristic.

In an example of a hydroisomerization reaction, the catalyst is a silica/alumina-based zeolite comprising an impregnated platinum group metal, the reaction temperature is between about 250 ℃ to about 400 ℃ or about 275 ℃ to about 400 ℃, the reaction pressure is between about 10 bar to about 400 bar or about 10 bar to about 100 bar, and the hydrogen to hydrocarbon ratio is about 100 to about 1000 or about 400 to about 1000.

A side reaction of the hydroisomerization process is hydrocarbon cracking, which produces short chain hydrocarbons. The crude product of the hydroisomerization is a mixture of squalane and squalane derivatives (long-chain hydrocarbons) and short-chain hydrocarbons having a carbon number of less than 30. Squalane and squalane derivatives are separated from short chain hydrocarbons by distillation or any other separation technique known to those skilled in the art, such that the final product is a blend of C30 alkanes that may include any combination of one or more squalane derivatives (with or without squalane).

Preparation

The product of the hydroisomerization step is then formulated into a cosmetic, personal care or pharmaceutical composition according to conventional methods well known in the art. Cosmetic, personal care or pharmaceutical compositions may include one or more excipients, diluents or active ingredients, as will be readily determined by one of skill in the formulation methodology based on the end use of the composition.

In order that the invention described herein may be better understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of the present invention in any way.

Examples

Example 1:

kelbert electrolysis was performed using a feedstock blend of palmitic and stearic acids to produce a blend of C30-C34 hydrocarbons. A second kerb electrolysis was performed using only the palmitic acid feed to produce a blend of C30 hydrocarbons. The resulting hydrocarbons are each hydroisomerized using a silica/alumina based zeolite comprising impregnated platinum as catalyst at a reaction temperature between 275 ℃ and 400 ℃ and a reaction pressure between 10 bar and 100 bar. In each case, the ratio of hydrogen to hydrocarbon is between 400 and 1000. The alkane product is purified by distillation to remove short chain hydrocarbon products of the cracking side reactions.

Figure 1 shows a comparison of gas chromatograms of C30 alkane blends (produced from palm fatty acids only), C30-C34 blends (heavier emollients produced from a combination of palm and stearin fatty acids), and commercially available olive squalane. The blend made from the palmitic acid starting material matched squalane more closely than the blend made from the combination of palmitic and stearic acids, confirming that the process produced a blend of alkanes very close to squalane.

Comprising the blend (i) a C30-C34 alkane; and (ii) the organoleptic characteristics of the hydroisomerized material of C30 alkanes was compared to that of commercially purchased squalane. The test methods are given in the table below.

The results of this test are shown qualitatively in the spider graph of fig. 2. The results show that the C30 blend is surprisingly similar to commercial squalane in sensory characteristics, more similar than the C30-C34 blend, and would be expected to have more similar characteristics based on the narrow size range in the blend. Thus, the C30 blends produced according to the methods described herein can be used as a synthetic substitute for squalane extracted from natural sources.

All publications, patents and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Having thus described the invention, it will be apparent that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.