Fermentationally produced retinoid-containing compositions and methods of making and using same

Abstract

Disclosed herein are compositions of matter suitable for use in foods, feeds, pharmaceuticals and cosmetic care products, the compositions of matter comprising a retinoid component and fermentation residues thereof. In embodiments, the retinoid component is present in a weight ratio relative to the fermentation residue of 4: 1 or greater, where the retinoid contains cis-isomer and trans-isomer, where the cis-isomer is present in an amount of less than 3% by weight relative to the entire isomer mixture. Preferably, the composition is bio-based. Also described are biotechnological methods for producing the compositions otherwise described, as well as additional methods for processing such compositions into more stable, more commercially acceptable forms. Finally, foods, feeds, pharmaceuticals, and cosmetic care products incorporating the compositions described herein are also disclosed.

Description

Technical Field

[0001] The present invention relates to a retinol-containing composition produced by fermentation, a method for producing such a composition, a method for formulating such a fermentation-produced retinol-containing composition, and a preparation and (pre)product obtained by such methods.

[0002] Cross - reference to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 63 / 429,802, filed on December 2, 2022, the entire content of which is hereby incorporated by reference in its entirety as if fully set forth herein. Background Art

[0004] Retinols are a group of compounds that are isovitamins or chemically related to vitamin A. Due to the multiple health benefits associated with them, several retinols have been used in a variety of applications. Specifically, retinols have many important functions throughout the body, including roles in vision, regulation and differentiation of cell proliferation, bone tissue growth, immune function, and even activation of genes that may suppress tumors.

[0005] A particularly preferred retinol - vitamin A, is a fat-soluble vitamin and an essential nutrient for humans. The vitamin encompasses several chemically related naturally occurring compounds or metabolites that all contain a β-ionone ring, namely vitamins. Thus, the vitamin comprises a group of organic compounds that includes retinol, retinal, retinoic acid, and retinyl acetate. Vitamin A has a variety of uses, including for embryonic development and growth, maintaining the immune system and vision.

[0006] Vitamin A is present in foods in several major forms, such as retinol. It also exists as retinol or becomes a retinyl ester by binding to fatty acids, or as the carotenoids α-carotene, β-carotene, γ-carotene, and lutein β-cryptoxanthin (all containing a β-ionone ring) in animal-derived foods, which act as provitamin A in herbivores and omnivores that possess the enzymes to cleave and convert provitamin carotenoids to retinal and then to retinol.

[0007] Vitamin A deficiency is common in developing countries. Deficiency can occur at any age, but is most common in preschool children and pregnant women, the latter due to the need to transfer retinol to the fetus. It is estimated that vitamin A deficiency affects approximately one-third of children under five years old globally, resulting in hundreds of thousands of cases of blindness and death from childhood diseases due to immune system failure.

[0008] Although vitamin A and its provitamins are biosynthetically produced by the breakdown of β-carotene in most animal species, industrial methods for their production rely on chemical synthesis. The first industrial synthesis of retinol was achieved by Hoffmann-La Roche in 1947. In the following decades, many other companies also developed their own processes. β-Ionone, synthesized from acetone, is a necessary starting point for all industrial syntheses. Each process involves extending the unsaturated carbon chain. Nevertheless, this chemical synthesis method tends to be energy-intensive and typically utilizes raw materials from petro-based sources.

[0009] Biosynthetic alternatives have started to emerge. This fermentation-dependent method tends to confer a significantly lower (i.e., approximately 30 - 70%) carbon footprint than its chemical analogues and can further incorporate starting materials from bio-based - and thus more circular - sources.

[0010] Some methods utilize genetically engineered yeast species (such as Saccharomyces cerevisiae) to synthesize retinal and retinol using xylose as the starting substrate. This is achieved by having the yeast first synthesize β-carotene and then using the cleavage enzyme β-carotene 15,15'-dioxygenase to produce retinal.

[0011] However, DSM IP Assets B.V. has described in, for example, WO2022090548 other attempts to use bio-based carbon sources during fermentation to produce biosynthetic sources of isoprenoids, particularly retinoids (such as via oleaginous yeasts, including Yarrowia lipolytica).

[0012] Regardless of the manufacturing method employed, retinoids, especially vitamin A and its provitamins, especially retinol, are extremely sensitive to oxidation and can become self-heating in an oxygen-rich environment. In addition to causing degradation of the potency, bioavailability, and / or efficacy of products associated with retinoids, the oxidation of retinoids can also cause fires and other safety issues. Therefore, such industrially produced materials must be prepared and transported at low temperatures and in an oxygen-free atmosphere. When prepared as dietary supplements or food additives, retinol is often stabilized as the ester derivatives retinol acetate or retinol palmitate, which tend to be slightly more oxidation-stable. Further, it is highly desirable to minimize the amount of impurities that, either by themselves or in combination with various retinoids, accelerate the degradation and / or oxidation process.

[0013] Notwithstanding the foregoing, there remains a need to formulate and provide retinoid-containing compositions having at least one of the following: contributing to greater circularity due to a high biobased content; conferring a lower carbon footprint, especially when compared to such compositions synthesized industrially chemically; and which can provide excellent oxidative stability, preferably comparable or even superior to current industrially chemically synthesized alternatives. Additionally or alternatively, there is a need to provide fermentatively produced retinoid-containing compositions that are tuned to achieve excellent and / or improved performance in their end-use applications. One such example of this is a formulation for excellent and / or improved antimicrobial efficacy, which is important in a variety of cosmetic applications including, but not limited to, preventing / treating / alleviating the symptoms of acne or malodor caused by sweating. The foregoing ensures that such retinoid-containing compositions are commercially applicable to a variety of products in a number of food and beverage (hereinafter referred to as "food"), animal feed (hereinafter referred to as "feed"), pharmaceutical, and personal care applications. SUMMARY OF THE INVENTION

[0014] The present inventors have found herein that when the inventions according to the various aspects and / or embodiments described herein are employed, one or more of the above problems can be solved. Accordingly, several aspects and embodiments of the present invention are described herein. A first aspect is a substance composition for use in food, feed, pharmaceuticals or beauty care products, the substance composition comprising: (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the entire retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%. According to a further embodiment of the first aspect, the substance composition is configured to comprise one or more specific retinoids, including retinyl acetate, retinol or retinyl palmitate, and / or the fermentation residue is configured to comprise one or more of fatty acid retinyl ester (FARE), retinal, retinol, farnesol, fermentation carbon source and / or β-carotene as different amounts of fermentation residue. In another embodiment of the first aspect, the composition is configured such that it has a specified amount of the cis isomer of the FARE and retinoid mixture. In yet a further embodiment, the ratio of the retinoid component (i) to the fermentation residue (ii) is tuned to a range different from the range specified according to the first embodiment, and / or the composition is configured to have a different level of bio-based carbon content. In still other embodiments, the composition exists in crystalline form, optionally further having a specified average crystal length, or the composition may exist as a "wet crystal" or even as an emulsion in oil together with a solvent.

[0015] A second aspect of the present invention is a method for fermenting to produce a retinoid-containing composition, the method comprising the steps of: (a) culturing a microorganism under conditions permitting the production of a fermentation product; (b) separating the fermentation product to produce a separated retinoid-containing composition; wherein the separated retinoid-containing composition comprises (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue, and wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the entire retinoid component.

[0016] A third aspect of the present invention is a method for preparing a food, feed, pharmaceutical or personal care (pre) product, the method comprising the steps of: (1) providing a substance composition comprising, consisting of or consisting essentially of the following: (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the entire retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%; and (2) formulating the substance composition to produce a formulation.

[0017] A fourth aspect of the present invention is a beadlet or extrudate produced by a method according to any embodiment of the third aspect of the present invention, and / or a beadlet or extrudate incorporating a substance composition according to any embodiment of the first aspect of the present invention, and / or a beadlet or extrudate produced by a method according to any embodiment of the second aspect of the present invention.

[0018] A fifth aspect of the present invention is a food, feed, pharmaceutical or personal care product, the food, feed, pharmaceutical or personal care product comprising any one of the following: an extrudate and / or a beadlet according to the fourth aspect; and / or an extrudate and / or a beadlet produced by a method according to any embodiment of the third aspect; and / or an extrudate and / or a beadlet comprising a substance composition according to any embodiment of the first aspect; and / or an extrudate and / or a beadlet produced by a method according to any method of the second aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 A micrograph image of a crystalline form of a fermentation-produced retinoid-containing composition according to one or more aspects and / or embodiments of the present invention (Example 1) is shown, with selected crystal length measurements indicated on the micrograph image; and

[0020] Figure 2 A micrograph image of a crystalline form of a fermentation-produced retinoid-containing composition according to one or more aspects and / or embodiments of the present invention (Example 2) is shown, with selected crystal length measurements indicated on the micrograph image;

[0021] Figure 3Shows a micrograph image of a crystalline form of a fermentation-produced retinoid-containing composition according to one or more aspects and / or embodiments of the present invention (Example 3), with selected crystal length measurements indicated on the micrograph image;

[0022] Figure 4 Shows a micrograph image of a crystalline form of a fermentation-produced retinoid-containing composition according to one or more aspects and / or embodiments of the present invention (Example 4), with selected crystal length measurements indicated on the micrograph image; and

[0023] Figure 5 Shows a micrograph image of a crystalline form of a chemically synthesized retinoid-containing composition (Example 5), with selected crystal length measurements indicated on the micrograph image. Detailed Description

[0024] A first aspect of the present invention is a substance composition for use in food, feed, pharmaceuticals, or cosmetic care products, the substance composition comprising, consisting of, or consisting essentially of the following substances:

[0025] (i) A retinoid component comprising a mixture of cis and trans isomers, and

[0026] (ii) Its fermentation residue;

[0027] Wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue;

[0028] Wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the entire retinoid component;

[0029] Optionally, wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%.

[0030] The composition according to the first aspect of the present invention contains both (i) a retinoid component and (ii) its fermentation residue. As used herein, "retinoid component" refers to a specific retinoid compound, which is the major retinoid present after the fermentation process. The term "retinoid" as used herein preferably refers to a compound of formula (I) (without any indication of stereochemistry):

[0031]

[0032] Wherein

[0033] R is -CHO, -CH2OH, -COOH, -CH(R 1) 2, -CH2OR 2 , -COOR 3 , -CONHR 4 , or -CO(NR 4 )2,

[0034] R 1 is independently a lower alkoxy group, or R 1 ' and R 1 " together form a lower alkylenedioxy group,

[0035] R 2 is an alkanoyl or aroyl group,

[0036] R 3 is an alkyl, aryl or aralkyl group; and

[0037] R 4 , R 4' and R 4" are independently hydrogen, an alkyl, aryl or aralkyl group;

[0038] wherein the term "lower alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy or propoxy;

[0039] The term "lower alkylenedioxy" is a group that also contains 1 to 6 carbon atoms, such as methylenedioxy or ethylenedioxy, and wherein the alkyl or alkylenyl moiety can be straight-chain or branched, depending on the number of carbon atoms;

[0040] The term "alkanoyl" refers to a straight-chain or branched alkanoyl group having 1 to 18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl and palmitoyl;

[0041] The term "aroyl" refers to aromatic carboxylic acids having 7 and 11 carbon atoms, including benzoyl or naphthoyl, respectively;

[0042] The term "alkyl" is a straight-chain or branched alkyl group having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl or octadecyl;

[0043] The term "aryl" is phenyl or naphthyl, either alone or as part of an "aralkyl"; and

[0044] The term "aralkyl" encompasses groups that have 1 to 4 carbon atoms in the aliphatic part, such as benzyl and phenylpropyl.

[0045] Specifically, the compound according to formula (I) as defined herein is selected from vitamin A and / or its derivatives, including but not limited to one or more retinols, said retinols being selected from retinol, retinal, retinoic acid, and derivatives such as esters, acetals, and / or amides, especially esters, more especially retinol acetate. Particularly suitable retinyl esters according to the invention are retinyl acetate, retinyl propionate, retinyl linoleate, retinyl palmitate, retinyl retinoate, and / or retinyl formyl aspartate. Preferably, the compound according to formula (I) is selected from retinol and / or retinyl esters, especially retinol and / or retinol acetate. In a preferred embodiment, the retinoid component consists of retinol. In another preferred embodiment, the retinoid component consists of retinol acetate.

[0046] It should be understood that the retinoid component may give rise to multiple isotypes or isomers of retinoids. In such a case, the retinoid component will contain all such isomers. If the fermentation process yields multiple retinoid substances, it is meant herein that only the most predominantly present retinoid (by weight %) is construed as the retinoid component.

[0047] By extension, it should be understood that for the purposes of the present invention, all other retinoids produced will not be construed as part of the "retinoid component". Instead, such retinoids will form part of the "fermentation residue". In addition to this, the fermentation residue is herein also construed as including any other biosynthetic non-retinoid substances still produced by the microorganism utilized during the fermentation process, such as precursor compounds like β-carotene, or various types of derived compounds such as fatty acid retinyl esters (FARE). Such substances, insofar as they are produced by the microorganism itself, rather than via the introduction of foreign substances into the process, may be referred to herein as "internal" fermentation residues.

[0048] However, in addition to other retinoids not produced by the microorganism, the fermentation residue may additionally contain any other substances or materials as a result of the processes for culturing, fermenting, and isolating the desired retinoid. Thus, this includes any "external" impurities or by-products introduced into the composition by virtue of the broader fermentation and extraction processes, including but not limited to: residual amounts of carbon sources used to feed the retinoid-producing microorganism, any chemical additives used in the fermentation vessel or process, filtration media, washing liquids, solvents, biomass, or any other distillates. When the composition is construed in the foregoing manner, the fermentatively produced and isolated active retinoid—along with all impurities associated therewith—may form a predetermined material composition of the "active" ingredient, which may subsequently be incorporated via a formulation process into one or more commercially viable (pre)products.

[0049] In an embodiment, the fermentation residue of the composition comprises one or more of FARE, retinol, retinol, farnesol, fermentable carbon source, and β-carotene.

[0050] It is well known that fermentation residues are generally unwanted "impurities" in the fermentation process. Specifically, it is generally recognized that for the production of retinoids by fermentation, especially the production of retinol acetate, unwanted "by-products" include, but are not limited to, retinol, retinol, FARE, or dihydro forms (such as dihydroretinol or dihydroretinol acetate), especially the formation of FARE, which should be reduced or eliminated. The present inventors have surprisingly found that certain fermentation residues (such as FARE) may not be as unwanted as previously thought and may actually contribute to oxidative stability if tuned in combination with one or more other factors. Specifically, the present inventors have surprisingly found that the FARE content may be far less harmful to reducing oxidative stability than the corresponding amount of retinoid cis isomers present in the retinoid component, and the importance of this FARE content is reduced to about one-tenth of the corresponding amount of retinoid cis isomers present in the retinoid component. Even more than that, the present inventors have also observed that retinoid-containing compositions with a small amount of FARE are associated with increased oxidative stability - or at least related to increased oxidative stability - compared to retinoid-containing compositions without FARE.

[0051] Accordingly, in an embodiment, the composition of the first aspect is configured to have a so-called "weighted" selected fermentation residue value (WSFRV), where WSFRV is determined according to the following formula:

[0052] WSFRV = C + 0.1 × F

[0053] where

[0054] C = the weight percentage of the cis isomers present relative to the total amount of the retinoid component (i) and the fermentation residue (ii), and

[0055] F = the weight percentage of the FARE present relative to the total amount of the retinoid component (i) and the fermentation residue (ii).

[0056] In certain embodiments, the WSFRV of the composition is configured to be between 0.1 and 2.5, or between 0.1 and 2.0, or between 0.1 and 1.0, or between 0.1 and 0.9, or between 0.4 and 2.5, or between 0.4 and 2.0, or between 0.4 and 1.0, or between 0.4 and 0.9, or between 0.6 and 2.5, or between 0.6 and 2.0, or between 0.6 and 1.0, or between 0.5 and 0.9.

[0057] As used herein, FARE means all fatty acid retinyl esters that are generally, but not necessarily, limited to those commonly understood in the fields to which the present invention applies. Three commonly produced FAREs in the fermentation production of various retinols include retinyl acetate, retinyl palmitate, and retinyl oleate. As used herein, if the retinoid component is a retinoid other than retinyl acetate, retinyl palmitate, or retinyl oleate (e.g., retinol), then each of retinyl acetate, retinyl palmitate, and retinyl oleate will be included as FARE in the fermentation residue. However, if retinyl acetate is produced as the retinoid component (i), then it will not be counted as FARE either. In this case, retinyl palmitate and retinyl oleate will still be so counted.

[0058] In other embodiments, the fermentation residue contains one or more FAREs, wherein the one or more FAREs are present in an amount less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt% relative to the total weight of the retinoid components present. In still other alternative embodiments, the FARE is present in an amount of between 0.05 - 4 wt%, or between 0.1 - 4 wt%, or between 0.15 - 4 wt%, or between 0.2 - 4 wt% FARE, or between 0.05 - 3 wt%, or between 0.1 - 3 wt%, or between 0.15 - 3 wt%, or between 0.2 - 3 wt% FARE; or between 0.05 - 2 wt%, or between 0.1 - 2 wt%, or between 0.15 - 2 wt%, or between 0.2 - 2 wt% FARE; or between 0.05 - 1 wt%, or between 0.1 - 1 wt%, or between 0.15 - 1 wt%, or between 0.2 - 1 wt% FARE relative to the total retinoid components.

[0059] In other embodiments, the composition is configured such that, instead of the WSFRV as described above, it has a mixture of both the cis and trans isomers of the retinoid component, preferably wherein the retinoid component consists of retinyl acetate or retinol, and wherein the cis isomer is present in an amount of less than 1% by weight relative to the total weight of the mixture of the cis and trans isomers.

[0060] and / or

[0061] wherein, relative to the total weight of the retinoid component, FARE is present in an amount of less than 3.5% by weight, or less than 1.5% by weight.

[0062] In various embodiments, the retinoid component comprises a mixture of cis and trans isomers, wherein the cis isomer is present in an amount, by weight, relative to the total weight of the mixture

[0063] between 0.1 - 3% by weight, or between 0.2 - 3% by weight, or between 0.4 - 3% by weight, or between 0.5 - 3% by weight; or

[0064] between 0.1 - 2.5% by weight, or between 0.2 - 2.5% by weight, or between 0.4 - 2.5% by weight, or between 0.5 - 2.5% by weight; or

[0065] between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.4 - 2% by weight, or between 0.5 - 2% by weight; or

[0066] between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.4 - 1.5% by weight, or between 0.5 - 1.5% by weight; or

[0067] between 0.1 - 1% by weight, or between 0.2 - 1% by weight, or between 0.4 - 1% by weight, or between 0.5 - 1% by weight; or

[0068] between 0.1 - 0.9% by weight, or between 0.2 - 0.9% by weight, or between 0.4 - 0.9% by weight, or between 0.5 - 0.9% by weight.

[0069] Regarding the retinoid component (i), as described above, it should be understood that both cis and trans isomers of a particular retinoid will be present. As used herein, the terms "trans-retinyl acetate", "trans-retinol", "trans-retinal", etc. are known to those skilled in the art and conform to the IUPAC-IUB nomenclature, and mean that all double bonds in such retinyl acetate, retinol, retinal compounds (including compounds according to formula (I)) are in the trans configuration. The terms "trans-retinyl ester", especially "trans-retinyl acetate", and "all-trans-retinyl ester", especially "all-trans-retinyl acetate", are used interchangeably herein.

[0070] Thus, if any one of several double bonds is not in the trans configuration but in the cis configuration, it should be understood herein that all such isomers are considered cis isomers herein (e.g., cis-retinyl acetate or cis-retinol or cis-retinal, depending on the desired retinoid component (i)), and are thus included in the determination of "cis isomer %" or "cis isomer content". Conversely, only those isomers having all double bonds in the trans configuration will be interpreted as trans isomers herein.

[0071] For example, the cis-configured retinoid isomers encompassed by the present invention include, but are not limited to, 9-cis-retinol, 11-cis-retinol, 13-cis-retinol, 9,13-dicis-retinol, 11,13-dicis-retinol, 13-cis-3,4-dehydroretinol, 9-cis-3,4-dehydroretinol, 9,13-dicis-3,4-dehydroretinol, 13-cis-retinal, 11-cis-retinal, 11,13-dicis-retinal, 9,13-dicis-retinal, 9-cis-retinal, 13-cis-3,4-dehydroretinal, 11,13-dicis-3,4-dehydroretinal, and the corresponding cis forms of retinyl acetate (for a review, see, for example, Table 1 in Gundersen and Blomhoff, J. Chromatogr. A 935, 13-43, 2001).

[0072] The present inventors have found that retinoid-containing compositions having a retinoid component configured to respectively possess certain contents of cis and trans isomers can confer certain advantages to the associated composition or (pre)-product. As non-limiting potential advantages, such compositions can be used as antimicrobial agents having a cis / trans ratio as defined herein. Specifically, when using retinyl acetate as the retinoid component, it has been observed that the composition is particularly suitable as an antimicrobial agent against Cutibacterium acnes, Corynebacterium xerosis, and Malassezia, preferably Malassezia furfur, while retinol is particularly suitable as an antimicrobial agent against Cutibacterium acnes.

[0073] Assuming that the response factors of all isomers are the same, the cis / trans ratio as given herein refers to the weight % ratio of the sum of the corresponding all-trans isomer to the all-cis isomer in the retinol / retinol mixture according to formula (I) determined by HPLC. In a preferred embodiment of the first aspect of the present invention, the cis / trans ratio of the compound according to formula (I) is less than 0.03, or less than 0.02, or less than 0.01, or the cis / trans ratio is 0.0099, 0.0095, 0.009, 0.0085, 0.008, 0.0075, 0.007, 0.0065, 0.006, 0.0055, 0.005, 0.0049, 0.0045, 0.0043, 0.004, 0.0035, 0.003, 0.0028, 0.0025, 0.0022, 0.002, 0.0018, 0.0015, 0.001, 0.0005 or less, such as 0.0001 or less, more preferably in the range of 0.0099 to 0.0001, 0.008 to 0.001, 0.007 to 0.002, 0.0099 to 0.001, 0.005 to 0.001, 0.005 to 0.0001, 0.005 to 0.0005, 0.006 to 0.001, 0.009 to 0.0001, 0.008 to 0.0001, 0.006 to 0.0001, 0.0055 to 0.0001, 0.005 to 0.002, 0.007 to 0.0001, 0.0045 to 0.0001, 0.004 to 0.0001, 0.0035 to 0.0001, 0.003 to 0.0001, 0.005 to 0.0025, 0.004 to 0.0005, 0.006 to 0.0005, 0.006 to 0.0008, 0.006 to 0.0015, 0.006 to 0.002, 0.006 to 0.003, 0.006 to 0.0004, 0.006 to 0.0025, and most preferably the cis / trans ratio is from 0.0049 to 0.0025.

[0074] In a preferred embodiment, the retinoid according to formula (I) is retinyl acetate, in particular with a cis / trans ratio of less than 0.03, or less than 0.02, or less than 0.01, preferably 0.0099, 0.0095, 0.009, 0.0085, 0.008, 0.0075, 0.007, 0.0065, 0.006, 0.0055, 0.005, 0.0049, 0.0045, 0.0043, 0.004, 0.0035, 0.003, 0.0028, 0.0025, 0.0022, 0.002, 0.0018, 0.0015, 0.001, 0.0005 or less, such as 0.0001 or less, more preferably in the range from 0.0099 to 0.0001, 0.008 to 0.001, 0.007 to 0.002, 0.009 to 0.0001, 0.008 to 0.0001, 0.005 to 0.001, 0.005 to 0.0001, 0.005 to 0.0005, 0.006 to 0.001, 0.006 to 0.0001, 0.0055 to 0.0001, 0.007 to 0.0001, 0.0045 to 0.0001, 0.005 to 0.002, 0.004 to 0.0001, 0.0035 to 0.0001, 0.003 to 0.0001, 0.005 to 0.0025, 0.006 to 0.0005, 0.006 to 0.0008, 0.006 to 0.0015, 0.006 to 0.002, 0.006 to 0.003, 0.006 to 0.0004, 0.006 to 0.0025, 0.004 to 0.0005, and most preferably retinyl acetate with a cis / trans ratio of 0.0049 to 0.0025.

[0075] In alternative embodiments, the cis / trans ratio may be expressed differently, for example, by the total percentage of the cis isomer content. Thus, in various embodiments, the retinoid component comprises a mixture of cis and trans isomers, wherein the cis isomer is present in the following amounts by weight relative to the weight of the entire mixture

[0076] between 0.1 - 3% by weight, or between 0.2 - 3% by weight, or between 0.4 - 3% by weight, or between 0.5 - 3% by weight; or

[0077] between 0.1 - 2.5% by weight, or between 0.2 - 2.5% by weight, or between 0.4 - 2.5% by weight, or between 0.5 - 2.5% by weight; or

[0078] between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.4 - 2% by weight, or between 0.5 - 2% by weight; or

[0079] between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.4 - 1.5% by weight, or between 0.5 - 1.5% by weight; or

[0080] between 0.1 - 1% by weight, or between 0.2 - 1% by weight, or between 0.4 - 1% by weight, or between 0.5 - 1% by weight; or

[0081] between 0.1 - 0.9% by weight, or between 0.2 - 0.9% by weight, or between 0.4 - 0.9% by weight, or between 0.5 - 0.9% by weight.

[0082] Compositions containing retinol acetate with a cis / trans ratio as described above can be used for preventing, treating or alleviating the symptoms of acne, pruritus, pityriasis versicolor, dandruff formation, seborrheic dermatitis, atopic dermatitis, psoriasis and / or malodor caused by sweat, and can in particular be used as an antimicrobial agent against Propionibacterium acnes, Corynebacterium xerosis and / or Malassezia spp., preferably Malassezia furfur.

[0083] In a preferred embodiment, the retinoid according to formula (I) is retinol, in particular with a cis / trans ratio of less than 0.03, or less than 0.02, or less than 0.01, preferably with a cis / trans ratio of 0.0099, 0.0095, 0.009, 0.0085, 0.008, 0.0075, 0.007, 0.0065, 0.006, 0.0055, 0.005, 0.0049, 0.0045, 0.0043, 0.004, 0.0035, 0.003, 0.0028, 0.0025, 0.0022, 0.002, 0.0018, 0.0015, 0.001, 0.0005 or less, such as 0.0001 or less, more preferably in the range of 0.0099 to 0.0001, 0.008 to 0.001, 0.007 to 0.002, 0.0099 to 0.001, 0.005 to 0.001, 0.005 to 0.0001, 0.005 to 0.0005, 0.006 to 0.001, 0.009 to 0.0001, 0.008 to 0.0001, 0.006 to 0.0001, 0.0055 to 0.0001, 0.005 to 0.002, 0.007 to 0.0001, 0.0045 to 0.0001, 0.004 to 0.0001, 0.0035 to 0.0001, 0.003 to 0.0001, 0.005 to 0.0025, 0.004 to 0.0005, 0.006 to 0.0005, 0.006 to 0.0008, 0.006 to 0.0015, 0.006 to 0.002, 0.006 to 0.003, 0.006 to 0.0004, 0.006 to 0.0025, and most preferably retinol with a cis / trans ratio of 0.003. A composition containing retinol with the above cis / trans ratio can be used for preventing, treating, and / or alleviating the symptoms of acne, and in particular can be used as an antimicrobial agent against Propionibacterium acnes.

[0084] The retinoid according to formula (I), in particular the retinyl ester according to the present invention, preferably a mixture of retinyl acetate and / or cis and trans isomers of retinol, can be prepared by admixing the corresponding all-trans isomer with one or more cis isomers obtained by chemical or biological methods. Methods for preparing such all-trans and / or cis isomers are well known to those skilled in the art. Alternatively, a mixture of the isomer ratios can be prepared by appropriately adjusting the method.

[0085] Advantageously, in a preferred embodiment of the first aspect of the present invention, the retinoid, in particular the retinyl ester such as retinyl acetate and / or retinol, is biosynthesized by a fermentation process.

[0086] In certain embodiments, a mixture and / or composition comprising cis and trans isomers of retinoids as defined herein, in particular retinyl esters, preferably a mixture and / or composition of retinyl acetate and / or retinol, is produced during a fermentation process using a suitable retinoid-producing host cell (e.g., a bacterial or fungal cell) (see, e.g., Sun et al., ACS Synth. Biol., September 20, 2019; 8(9):2131-2140; Jang et al., Microbial Cell Factories 2011, 10:59), wherein the cell expresses a corresponding enzyme, e.g., a trans-selective enzyme, i.e., beta-carotene oxidase (BCO), which is involved in the biosynthesis of retinol by converting beta-carotene into retinal, which can be further enzymatically converted into retinol and / or retinyl esters, in particular retinyl acetate. Ethanol, corn sugar, or corn oil, all of which are derived from agricultural production, is fed into the fermentation. The fermentation product comprising retinyl esters, in particular retinyl acetate, can be extracted in the aliphatic phase and then purified to the crystalline form.

[0087] Advantageously, the trans retinyl esters, in particular trans retinyl acetate, and / or trans retinol produced by fermentation can be heat-treated to form cis retinyl esters, in particular cis retinyl acetate, and / or cis retinol, to achieve the appropriate levels mentioned in all embodiments of the present invention (see, e.g., McBee et al., JBC, Vol. 276, No. 51, pp. 48483-48493, 2001).

[0088] As used herein, the term "bio-produced" or "fermentation-produced" means retinoids, especially retinyl esters, especially retinyl acetate and / or retinol, produced by means of a biotechnological process, such as a fermentation process, said fermentation process comprising culturing a suitable host cell (producing carotenoids and / or retinoids), said host cell expressing the corresponding enzymes involved in converting a suitable carbon source into retinyl esters as defined herein, especially retinyl acetate and / or retinol, wherein said host cell may be selected from bacteria, fungi, especially yeasts, plants or algae. "Bio-produced", "biologically-derived" and "biologically produced" are used synonymously herein. Thus, the bio-produced retinoids according to formula (I) consist of the conversion of carbon from atmospheric carbon dioxide (also referred to as carbon of atmospheric origin) into sugars and starches by green plants. It also includes the use of isolated and / or immobilized enzymes in the process for generating a mixture of retinoids as defined herein, such as enzymes capable of selectively catalyzing the formation of retinoids, especially retinyl esters, preferably retinyl acetate and / or retinol, in a specific trans / cis ratio in the mixture as defined herein.

[0089] In an embodiment, the C-14 / C-12 isotope ratio of a "bio-based" compound is in the range from 1:0 to greater than 0:1, in contrast to the C-14 / C-12 isotope ratio of a fossil-based compound which is 0:1. The bio-based content of a compound can be measured by known radiocarbon and isotope ratio mass spectrometry or accelerator mass spectrometry, such as ASTM test method D6866-05, wherein the C-14 / C-12 isotope ratio in a sample is measured and compared to a standard 100% bio-based material to derive the percentage of the bio-based content of the sample.

[0090] As used herein, "carbon of atmospheric origin" refers to carbon atoms from carbon dioxide molecules that have been free in the Earth's atmosphere in recent decades. The mass of such carbon is identifiable by the presence of specific radioactive isotopes as described herein. "Green carbon", "atmospheric carbon", "environmentally friendly carbon", "life cycle carbon", "non-fossil fuel-based carbon", "non-petroleum-based carbon", "carbon of atmospheric origin" and "bio-based carbon" are used interchangeably herein.

[0091] According to certain preferred embodiments of the present invention, retinoids, particularly retinol and / or retinyl esters, preferably retinyl acetate, are advantageously produced only from organic, renewable, bio-based raw materials, particularly raw materials produced by fermentation. Therefore, retinol and / or retinyl esters, preferably retinyl acetate, have the characteristic of zero anthropogenic CO2 emissions upon biodegradation because all CO2 molecules released during the degradation of such "fermentation-derived" or "fermentation-produced" retinoids have an atmospheric origin. Thus, the net release of CO2 into the atmosphere is zero. Accordingly, in a preferred embodiment, the fermentation carbon source comprises, consists of, or consists essentially of a bio-based carbon source.

[0092] In various embodiments of the first aspect, the bio-based carbon content of the substance composition is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%, or even about 100%; in still other embodiments, the bio-based carbon content of the retinoid component (i) and its fermentation residue (ii) is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%, or even about 100%. The bio-based content can be determined by any suitable means, such as via ASTM D6866-20 or by appropriate 14 C isotope characterization, such as the methods described elsewhere herein below.

[0093] As described above, the fermentation residue can contain a variety of substances, such as FARE, β-carotene, retinol, retinal, and / or one or more of the fermentation carbon sources. In other embodiments, particularly where the retinoid component is retinyl acetate, the fermentation residue can contain each of FARE, β-carotene, retinol, retinal, and the fermentation carbon source.

[0094] A variety of retinol isotopes can be included as retinol, such as all-E-retinol. Similarly, a variety of retinal isotopes can also be used, such as 9Z-retinal. The inventors have surprisingly observed that a composition containing 9Z-retinal can exhibit improved oxidative stability when compared to a composition without such a fermentation residue. However, interestingly, the oxidative stability appears to be negatively correlated with the amount of 9Z-retinal present in the retinoid-containing composition.

[0095] Thus, in various embodiments of the first aspect, the fermentation residue contains 9Z-retinal, but wherein 9Z-retinal is present in an amount of less than 10 wt%, or less than 8 wt%, or less than 6 wt%, or less than 5 wt%, or less than 3 wt% relative to the total weight of the retinoid components present. In other embodiments, the composition expressly contains 9Z-retinal, wherein 9Z-retinal is between 0.1 - 10 wt%, or between 0.5 wt% to 10 wt%, or between 1 wt% to 10 wt%, or between 1.5 wt% to 10 wt% relative to the total weight of the retinoid components present; or between 0.1 - 8 wt%, or between 0.5 wt% to 8 wt%, or between 1 wt% to 8 wt%, or between 1.5 wt% to 8 wt% of 9Z-retinal; or

[0096] 9Z-retinal between 0.1 - 6 wt%, or between 0.5 wt% to 6 wt%, or between 1 wt% to 6 wt%, or between 1.5 wt% to 6 wt%; or between 0.1 - 5 wt%, or between 0.5 wt% to 5 wt%, or between 1 wt% to 5 wt%, or between 1.5 wt% to 5 wt%; or between 0.1 - 3 wt%, or between 0.5 wt% to 3 wt%, or between 1 wt% to 3 wt%, or between 1.5 wt% to 3 wt%.

[0097] Yet another potential component of the fermentation residue is β-carotene. The presence of β-carotene is believed to impart a more orange or pinkish hue to the fermentatively produced retinoids when compared to their chemically synthesized analogues. β-carotenes confer health benefits of their own and thus their presence as a fermentation residue in a retinoid-containing composition is not necessarily considered undesirable and may be desirable depending on the intended end-use application. Thus, in embodiments, the fermentation residue contains β-carotene, wherein the β-carotene is present in an amount of less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt%, or less than 0.5 wt% relative to the total weight of the retinoid components present.

[0098] However, in other embodiments of the first aspect, the composition contains β-carotene between 0 - 4 wt%, or between 0.2 - 4 wt%, or between 0.5 - 4 wt%, or between 1 - 4 wt% relative to the total weight of the retinoid components present, or

[0099] β-carotene in an amount between 0 - 3% by weight, or between 0.2 - 3% by weight, or between 0.5 - 3% by weight, or between 1 - 3% by weight, or

[0100] β-carotene in an amount between 0 - 2% by weight, or between 0.2 - 2% by weight, or between 0.5 - 2% by weight, or between 1 - 2% by weight, or

[0101] β-carotene in an amount between 0 - 1% by weight, or between 0.2 - 1% by weight, or between 0.5 - 1% by weight, or

[0102] β-carotene in an amount between 0 - 0.5% by weight, or between 0.2 - 0.5% by weight.

[0103] Another potential component of the fermentation residue is farnesol. Farnesol has been identified as a potential skin irritant and as such, its presence in a retinoid-containing composition is undesirable. Therefore, it is preferred to limit as much as practical the amount of farnesol present in the retinoid-containing composition, e.g., below the detection limit of many standard analytical techniques (e.g., less than 0.1% by weight relative to the entire composition with which it is associated). Thus, in an embodiment, the composition comprises farnesol in an amount between 0 - 10,000 ppm, or between 2 - 10,000 ppm, or between 5 - 10,000 ppm, or between 10 - 10,000 ppm, or between 100 - 10,000 ppm relative to the total weight of the retinoid component present; or

[0104] farnesol in an amount between 0 - 5,000 ppm, or between 2 - 5,000 ppm, or between 5 - 5,000 ppm, or between 10 - 5,000 ppm, or between 100 - 5,000 ppm; or

[0105] farnesol in an amount between 0 - 1,000 ppm, or between 2 - 1,000 ppm, or between 5 - 1,000 ppm, or between 10 - 1,000 ppm, or between 100 - 1,000 ppm; or

[0106] farnesol in an amount between 0 - 100 ppm, or between 2 - 100 ppm, or between 5 - 100 ppm, or between 10 - 100 ppm. In a particularly preferred embodiment, the composition is free or substantially free of farnesol.

[0107] Another potential fermented residue component includes dihydroretinols, including retinol and / or retinyl acetate, specifically in the range of 0.2 wt% to 0.01 wt% or less, such as 0.2 wt%, 0.18 wt%, 0.16 wt%, 0.15 wt%, 0.14 wt%, 0.12 wt%, 0.1 wt%, 0.05 wt%, 0.01 wt% or less, preferably in the range of 0.2 wt% to 0.1 wt%, 0.17 wt% to 0.06 wt%, 0.1 wt% to 0.05 wt%, 0.04 wt% to 0.01 wt%, more preferably the percentage is 0.1 wt% or less, all based on the total components within the total fermented retinoid-containing composition. Also preferably, the percentage of retinyl acetate is about 0.05% or less, particularly about 0.01% or less, based on the total components within the composition.

[0108] Yet another potential fermented residue component is the unconsumed raw material or fermentation carbon source. As described above, since it is desired to maximize the recyclability of the resulting retinoid composition of this carbon source, it is desirable to utilize a biological carbon source. In WO2022090548A1 a variety of carbon sources suitable for retinoid fermentation are described, and this patent is hereby incorporated by reference in its entirety as if fully set forth herein.

[0109] Specifically, suitable carbon sources to be used in the present invention can be selected from straight-chain alkanes, free fatty acids, including triglycerides, particularly vegetable oils, such as those selected from the group consisting of oils derived from corn, soybean, olive, sunflower, canola, cottonseed, rapeseed, sesame, safflower, grape seed or mixtures thereof, including the corresponding free fatty acids, such as oleic acid, palmitic acid or linoleic acid. Suitable carbon sources can also be selected from ethanol, glycerol or glucose, and mixtures of one or more of the carbon sources listed above. In one embodiment, the present invention relates to a method for producing retinoids, particularly for producing retinyl acetate, i.e., a two-phase culture system in the presence of a lipophilic solvent as defined herein, wherein a host cell producing retinyl acetate, preferably an oil-producing yeast cell, such as a cell of the genus Yarrowia, is cultured under suitable culture conditions, wherein the lipophilic solvent is not consumed or evaporated during the fermentation process, and the lipophilic solvent is preferably selected from solvents that are commercially available as Isopar TM fluids, particularly selected from Isopar M, Isopar N, Isopar K, Isopar L, Isopar H or solvents having equivalent or identical properties but from other suppliers.

[0110] In an embodiment, the fermented carbon source is present in an amount less than 2 wt%, or less than 1 wt%, or less than 0.75 wt% relative to the total weight of the retinoid component present. In various other embodiments, the fermented carbon source is present in an amount between 0.05 wt% and 2 wt%, or between 0.1 wt% and 2 wt%, or between 0.2 wt% and 2 wt% relative to the weight of the retinoid component; or between 0.05 wt% and 1 wt%, or between 0.1 wt% and 1 wt%, or between 0.2 wt% and 1 wt%; or between 0.05 wt% and 0.5 wt%, or between 0.1 wt% and 0.5 wt%, or between 0.2 wt% and 0.5 wt%.

[0111] As an additional source of fermentation residues, so-called second-phase solvents may be present. These solvents are otherwise also referred to as lipophilic solvents and may include isoparaffins comprising mixtures of alkanes, cyclo paraffins, isoparaffins, cycloalkanes or dodecane. The solvents may be natural or synthetic. Examples of commercially useful solvents may be selected from Total (e.g. solvents), Shell (e.g. ShellSol TD or ShellSol T), Exxon Mobile (e.g. Isopar TM fluids, in particular e.g. Isopar M, Isopar N, Isopar H, Isopar K, Isopar L) or mixtures thereof or mixtures with isododecane isomers, which may be commercially available under the trade name AC365770010 (Acros Organics). Preferably, the second-phase solvent is selected from isoparaffins, including for example Isopar M, Isopar N, Isopar H, Isopar K, Isopar L and mixtures thereof, more preferably including Isopar N, Isopar L and / or Isopar M.

[0112] Another suitable lipophilic solvent, i.e. the second-phase solvent, which has minimal loss and / or disappearance during fermentation as defined herein and is to be used in the present invention, may be selected from lipophilic solvents including n-alkanes, isoparaffins, mixtures of hydrocarbons. The solvents may be natural or synthetic. Examples of commercially useful solvents may be selected from Exxon Mobil, which may be commercially available under the trade names Exxsol D60, D80, D95 or D110, for example.

[0113] It should be understood that useful solvents include the commercially available solvents listed above and corresponding solvents having the same or equivalent properties but known / available from other suppliers.

[0114] As used herein, the solvent has properties equivalent or identical to those of Isopar fluids including Isopar M, Isopar H, Isopar K, Isopar L, and is defined as a branched isomer, preferably a terminally methylated form of a straight-chain alkane, which contains six to twenty-six carbons and may be chemically coupled from smaller alkane precursors in strong acids, hydrogenated with H2 and a catalyst (such as nickel or platinum) to remove unsaturated moieties and trace aromatics. This is known among current industrial suppliers, such as Isopar (Exxon Mobil Chemical), Soltrol (Chevron Phillips Chemical Company), Shellsol OMS (Royal Dutch Shell), isooctane, and isododecane. Specifically, the use of Isopar M is preferred. The use of these substances in consumer products was outlined in a review by Johnson et al., Int J Toxicol. November–December 2012;3l(Suppl 6):269S-95S. As used herein, the solvent has properties equivalent or identical to those of Exxsol D60, D80, D95, D110. These Exxsol Ds are narrow-boiling fractions from cracked hydrocarbons that have been reduced by catalytic hydrogenation to remove aromatics and unsaturated moieties.

[0115] Thus, in an embodiment, the fermentation residue comprises an isoparaffinic fluid. In various related embodiments, the isoparaffinic fluid is present in an amount less than 3 wt%, or less than 2 wt%, or less than 1.5 wt%, or less than 1.25 wt% relative to the weight of the entire retinoid component (i) and its fermentation residue (ii), or wherein the isoparaffinic fluid is present in an amount between 0.1 - 2 wt%, or between 0.2 - 2 wt%, or between 0.5 - 2 wt%, or between 0.1 - 1.5 wt%, or between 0.2 - 1.5 wt%, or between 0.5 - 1.5 wt% relative to the weight of the entire retinoid component (i) and its fermentation residue (ii). In a preferred embodiment, if present, the isoparaffinic fluid comprises Isopar M, consists of Isopar M, or consists essentially of Isopar M.

[0116] The composition produced by fermentation of the first aspect is further tuned so as to have a certain amount of (i) and (ii) relative to each other. That is, in all embodiments of the first aspect, the retinoid-containing composition is configured such that the retinoid component is present at a weight ratio greater than 4:1 relative to its fermentation residue. Thus, it is desirable that the "active" ingredient, i.e., the retinoid component - which is preferably retinol, retinyl acetate or retinyl palmitate - is maintained at a very high level relative to its fermentation residue. Thus, in other embodiments, the weight ratio of the retinoid component to its fermentation residue is tuned to be greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or even greater than 25:1.

[0117] However, the inventors have still surprisingly found that the presence of the fermentation residue, particularly the specific types, amounts and ratios of fermentation residue components described elsewhere hereinabove, is still associated with beneficial effects on the compositions to which they are associated, such beneficial effects being, for example, excellent oxidative stability and / or antimicrobial efficacy. As will be described below, such benefits make the associated fermentation-produced retinoid-containing compositions particularly suitable for various formulation techniques, such as spray drying or extrusion. This subsequently facilitates their use in various foods, feeds, pharmaceuticals or personal care products or pre-products (hereinafter referred to as "(pre)-products"). Thus, in other embodiments, the retinoid component - which is preferably retinyl acetate, retinol or retinyl palmitate - is present relative to its fermentation residue in a weight ratio of between 4:1 and 100:1, or between 5:1 and 100:1, or between 6:1 and 100:1, or between 10:1 and 100:1, or between 20:1 and 100:1, or between 25:1 and 100:1; or

[0118] between 4:1 and 50:1, or between 5:1 and 50:1, or between 6:1 and 50:1, or between 10:1 and 50:1, or between 20:1 and 50:1, or between 25:1 and 50:1; or

[0119] between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or

[0120] between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:1.

[0121] Although the amounts, ratios, and types of fermented residue properties as described herein have not previously been recognized as being associated with one or more beneficial effects, it should be understood that those skilled in the art in the field to which the present invention pertains can tune or configure such fermented residue properties as appropriate through a variety of known methods and techniques. Specifically, the microorganisms utilized in the fermentation process can be selected and / or engineered to produce certain desired retinoid components and / or fermented residues, as described elsewhere herein. Also, the fermentation conditions can be modified accordingly, which further includes the selection and amount of various additives (i.e., antifoaming agents), or even the nature, type, and amount of the carbon source and / or lipophilic solvent used. Still further, those skilled in the art can readily tune the fermentation properties by means of the nature and number of downstream processing steps (e.g., the conditions for distillation, crystallization, filtration, and / or washing). The fermentation and separation conditions are further described elsewhere herein below.

[0122] The retinoid-containing composition according to the first aspect can be provided in any suitable form, however preferably produced in a manner that maximizes the ease of handling and transportation. In an embodiment, the retinoid-containing composition according to the first aspect is provided in crystalline form or in a predominantly crystalline form. As is intended herein, the crystalline form indicates that the composition is composed of solid materials or particles, the components of which are arranged in a highly ordered microstructure, thereby forming a lattice that extends in all directions. The inventors have found that the fermented residue properties may have an impact on the crystal structure formed. Figures 1 to 5 Multiple crystalline forms of the retinoid-containing composition are depicted. Figure 1 、 Figure 2 、 Figure 3 and Figure 4 respectively depict the crystalline forms of the fermented retinoid-containing compositions of Examples 1 to 4 used in the following examples. Among them, the crystals were determined to be approximately 200 - 900 microns or larger, and as in Figure 1 、 Figure 3 or Figure 4 have an elongated rhombic shape, or as depicted in Figure 2 have a more cubic shape with a crystal length of approximately 100 - 200 microns. In contrast, Figure 5 shows a significantly different crystalline structure obtained when using a chemically synthesized retinoid-containing composition without a fermented residue, in which case the crystals are typically approximately 100 - 200 microns or smaller. As can be seen, the average crystal size or length, as specifically determined by computerized automated micrograph analysis, varies between different fermented examples and chemical analogues. The inventors believe, without wishing to be bound by any theory, that the crystal size can affect the oxidative stability of the associated retinoid-containing composition.

[0123] Thus, in certain embodiments, the fermentatively produced retinoid-containing composition is in crystalline form, wherein the crystalline form comprises a plurality of crystals, and the average particle length D of the plurality of crystals, as determined by microscopy imaging methods 50 is greater than 100 microns, or greater than 200 microns, or greater than 300 microns, or greater than 400 microns, or between 100 - 1200 microns, or between 100 - 1000 microns, or between 100 - 800 microns, or between 200 - 1200 microns, or between 200 - 1000 microns, or between 200 - 800 microns.

[0124] The form presented by the fermentatively produced retinoid component can be the so-called "dry crystals" or "wet crystals". In the dry crystalline form, the composition typically lacks any liquid component and typically appears as and presents as a particulate or powder composition. In the wet crystalline form, the composition contains a large number of crystals but also contains a substantial amount of residual liquid, such as an associated solvent. Thus, the composition may look and behave like a slurry.

[0125] In yet another form, a composition containing retinoid (i) and fermentation residue (ii) is dissolved, mixed, and / or (most preferably) emulsified in an oil. In a preferred embodiment, if not in crystalline form, the retinoid component (i) and its fermentation residue (ii) are emulsified in a stabilized oil. This stabilized oil emulsion preferably contains any suitable oil, preferably an oil as a triglyceride, such as but not limited to vegetable oils and / or fats. In this sense, it should be understood that the oil will not be included as part of the fermentation residue component (ii).

[0126] As a suitable stabilizer, the stabilized emulsion preferably further contains a fat-soluble antioxidant and may contain but not limited to ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, tert-butylhydroxyquinoline, ethoxyquin, and / or ascorbyl esters of fatty acids. In this sense, it should be understood that the stabilizer will not be included as part of the fermentation residue component (ii).

[0127] As described above, the composition according to the first aspect is preferably configured to confer advantageous properties, such as excellent oxidative stability. Thus, when using one or more compositions configured as described above, the amount of the retinoid component (preferably retinyl acetate, retinol or retinyl palmitate), measured relative to the weight of the entire composition, is within 5 wt%, or within 4 wt%, or within 3 wt% of the amount of the retinoid component present in the composition after subjecting the composition to a thermal stability test, whereby the composition is heated to 105 degrees Celsius for 3 hours according to the method described elsewhere herein.

[0128] A second aspect of the invention is a method for fermentatively producing a retinoid-containing composition, the method comprising the steps of:

[0129] (a) culturing a microorganism under conditions permitting the production of a fermentation product;

[0130] (b) separating the fermentation product to produce a separated retinoid-containing composition;

[0131] wherein the separated retinoid-containing composition comprises

[0132] (i) a retinoid component comprising a mixture of cis and trans isomers, and

[0133] (ii) its fermentation residue;

[0134] wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue,

[0135] wherein the cis isomer is present in an amount by weight less than 3 wt% relative to the weight of the entire retinoid component.

[0136] Embodiments according to the second aspect of the invention relate to a fermentation process for producing a retinoid-containing composition. In all such embodiments, the process first involves the step of culturing a microorganism under conditions permitting the production of the desired fermentation product, which preferably comprises the retinoid component as described and used in all embodiments of the first aspect of the invention.

[0137] As will be understood by those skilled in the art, any suitable microorganisms can be used. Particularly suitable microorganisms include oil-producing fungi, such as fungi of the genus Yarrowia, because they are able to accumulate lipids to at least 20% of the cell dry weight of the microorganism; and additionally, as a result of genetic engineering, such microorganisms are able to produce the desired product, which can preferably accumulate to at least 1% of the cell dry weight of the microorganism. General methods for culturing carotenoids (precursors of retinoids) are described in US7851199 which is hereby incorporated by reference in its entirety as if fully set forth herein. The fermentative production of isoprenoids (a broader class of compounds including retinoids) is described in WO2022090548 which is also hereby incorporated by reference in its entirety as if fully set forth herein.

[0138] Those of ordinary skill in the art will readily recognize that there are a variety of yeast and fungal strains that naturally produce oil or naturally produce the desired retinoids. Any of such strains can be used as the host strain according to the second aspect of the present invention and can be engineered or otherwise manipulated to generate the oil-producing strains of the present invention, particularly retinoid-producing strains. Alternatively, strains that do not naturally produce oil or retinoids can also be employed. In addition, even when a particular strain has a natural ability to produce oil or produce retinoids, its natural ability can be adjusted as described herein to alter the production levels of lipids and / or retinoids. In certain embodiments, the engineering or manipulation of the strain will result in a change in the type of lipids and / or retinoids produced. For example, a strain may naturally produce oil and / or produce retinoids, yet engineering or modification of the strain can be employed to change the type of lipids accumulated and / or change the type of retinoids produced.

[0139] When selecting a particular yeast or fungal strain for use in accordance with the second aspect of the present invention, it is generally desirable to select a strain whose cultivation characteristics are suitable for commercial-scale production. For example, it is usually (but not always) desirable to avoid filamentous organisms or organisms with particularly unusual or stringent requirements for growth conditions. However, in cases where conditions for commercial-scale production that allow the use of filamentous organisms can be applied, these filamentous organisms can be selected as host cells. In some embodiments of the present invention, it will be desirable to utilize edible organisms as host cells because they can optionally be formulated directly as food or feed additives or as nutritional supplements as needed. For ease of production, some embodiments of the present invention utilize host cells that are genetically tractable, suitable for molecular genetics (e.g., can be efficiently transformed, especially with established or available vectors; can optionally incorporate and / or integrate multiple genes sequentially, for example; and / or have known gene sequences, etc.), have no complex growth requirements (e.g., require light), are mesophilic (e.g., prefer a growth temperature in the range of about 25 - 32 °C), are capable of assimilating a variety of carbon and nitrogen sources and / or are capable of growing to high cell densities. Additionally or alternatively, various embodiments of the present invention utilize host cells that grow as single cells rather than multicellular organisms (e.g., as mycelia).

[0140] Generally speaking, when it is necessary to utilize the natural oil-producing organisms according to the second aspect of the present invention, any modifiable and culturable oil-producing organisms can be adopted. In certain embodiments of the present invention, yeasts or fungi including but not limited to the following genera are adopted: Blakeslea, Candida, Cryptococcus, Cunninghamella, Lipomyces, Mortierella, Mucor, Phycomyces, Pythium, Rhodosporidium, Rhodotorula, Trichosporon, and Yarrowia. In certain specific embodiments, organisms of species including but not limited to Blakeslea trispora, Candida pulcherrima, Candida revkaufi, Candida tropicalis, Cryptococcus curvatus, Cunninghamella echinulata, Cunninghamella elegans, Cunninghamella japonica, Lipomyces starkeyi, Lipomyces lipoferus, Mortierella alpina, Mortierella isabellina, Mortierella ramanniana, Mortierella vinacea, Mucor circinelloides, Phycomyces blakesleanus, Pythium irregulare, Rhodosporidium toruloides, Rhodotorula glutinis, Rhodotorula gracilis, Rhodotorula graminis, Rhodotorula mucilaginosa, Rhodotorula pinicola, Trichosporon pullans, Trichosporon cutaneum, and Yarrowia lipolytica are used.

[0141] Those of ordinary skill in the art will understand that the choice of a particular host cell for use in accordance with embodiments of the second aspect of the present invention will also affect, for example, the choice of expression sequences to be utilized with any heterologous polypeptides to be introduced into the cell, and will also affect various aspects of the culture conditions, etc. Considerable knowledge exists regarding the different gene regulatory requirements, protein targeting sequence requirements, and culture requirements of different host cells to be utilized in accordance with the second aspect of the present invention (for Yarrowia, see, e.g., Barth et al., FEMS Microbiol Rev. 19:219, 1997; Madzak et al., J Biotechnol. 109:63, 2004; for Xanthophyllomyces, see, e.g., Verdoes et al., Appl Environ Microbiol 69:3728-38, 2003; Visser et al., FEMS Yeast Res 4:221-31, 2003; Martinez et al., Antonie Van Leeuwenhoek. 73(2):147-53, 1998; Kim et al., Appl Environ Microbiol. 64(5):1947-9, 1998; Wery et al., Gene. 184(1):89-97, 1997; for Saccharomyces, see, e.g., Guthrie and Fink Methods in Enzymology 194:1-933, 1991). In some aspects, for example, the targeting sequence (or closely related analog) of the host cell may be available for inclusion to direct a heterologous protein to subcellular localization. Thus, such useful targeting sequences can be added to heterologous sequences to achieve appropriate intracellular localization of activity. In other aspects (e.g., addition of a mitochondrial targeting sequence), heterologous targeting sequences (e.g., altering or removing a plant chloroplast targeting sequence from the source organism) may be eliminated or altered in the selected heterologous sequence.

[0142] Embodiments of the second aspect also relate to the step of separating the fermentation product to produce a separated retinoid-containing composition. As described above, the accumulation of liposomes in oleaginous organisms is typically induced by growing the relevant organisms in the presence of an excess carbon source and, for example, limiting nitrogen. Specific conditions for inducing such accumulation have previously been established for a variety of different oleaginous organisms (see, for example, Wolf (ed.) Non-conventional yeasts in biotechnology, Vol. 1, Springer-Verlag, Berlin, Germany, pp. 313-338; Lipids 18(9):623, 1983; Indian J. Exp. Biol. 35(3):313, 1997; J. Ind. Microbiol. Biotechnol. 30(1):75, 2003; Bioresour Technol. 95(3):287, 2004, each of which is incorporated herein by reference in its entirety).

[0143] Methods and systems for separating liposomes have been established for a variety of oleaginous organisms (see, for example, U.S. Patent Nos. 5,164,308; 5,374,657; 5,422,247; 5,550,156; 5,583,019; 6,166,231; 6,541,049; 6,727,373; 6,750,048; and 6,812,001, each of which is incorporated herein by reference in its entirety. Briefly, cells are typically recovered from the culture by spray drying, filtration, or centrifugation. In some cases, the cells are homogenized and then subjected to supercritical fluid extraction or solvent extraction (e.g., using solvents such as chloroform, hexane, methylene chloride, methanol, isopropanol, ethyl acetate, etc.), resulting in a crude oil suspension. This oil suspension can optionally be refined as known in the art. The refined oil can be used directly as a feed or food additive. Additionally or alternatively, retinoids can be separated from the oil using conventional techniques.

[0144] Given that retinoids are typically sensitive to oxidation, many embodiments of the present invention employ oxidation stabilizers (e.g., tocopherols, vitamin C; ethoxyquin; vitamin E, BHT, BHA, TBHQ, etc., or combinations thereof) during and / or after retinoid separation. Additionally or alternatively, microencapsulation (e.g., microencapsulation using proteins) can be employed to increase the physical barrier against oxidation and / or improve handling.

[0145] The separation of the fermentation product may further include one or more additional downstream processing steps. These steps include, but are not limited to, various processes and techniques for crystallization, distillation, filtration, and / or washing. Such methods are known and will be understood by those of ordinary skill in the art to which the present invention pertains.

[0146] Regardless of the specific types and natures of both the culturing step (a) and the separation step (b) of the embodiments according to the second aspect, the method is configured to produce a resulting retinoid-containing composition having: (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue, wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue, and wherein the cis isomer is present in an amount less than 3% by weight relative to the total retinoid component. It should be understood that the retinoid-containing composition produced in the embodiments of the second aspect will preferably be according to any of the embodiments described above with respect to the first aspect of the present invention.

[0147] Optionally, the method according to the second aspect further includes the step of combining the separated retinoid-containing composition, the retinoid-containing composition, the dry retinoid crystal composition, and / or the separated retinol product with one or more other additives. This can be done to create a stabilization formulation for subsequent transportation - certain non-limiting processes will be further described below - or to create a (pre)product for food, feed, pharmaceutical, or personal care applications.

[0148] A third aspect of the present invention is a method for preparing a food, feed, pharmaceutical, or personal care (pre)product, the method comprising the steps of:

[0149] (a) providing a material composition comprising, consisting of, or consisting essentially of

[0150] (i) a retinoid component comprising a mixture of cis and trans isomers, and

[0151] (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the total retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%; and

[0152] (b) formulating the material composition to produce a formulation, preferably for use as a food, feed, pharmaceutical, or personal care (pre)product.

[0153] According to an embodiment of the third aspect, the provided substance composition comprises, consists of, or consists essentially of: (i) a retinoid component comprising a mixture of cis and trans isomers; and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; wherein the cis isomer is present in an amount less than 3% by weight based on the weight of the whole retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%. Preferably, the provided composition is any fermented retinoid-containing composition produced by fermentation according to any embodiment of the embodiments of the first aspect of the present invention, and preferably is also provided by any method among the methods described in any embodiment of the second aspect.

[0154] For the provided compositions, it is often desirable to formulate such substance compositions in order to increase their suitability for storage, handling, and transportation, bioavailability, miscibility, or other properties for subsequent suitability - whether containing (pre-product) or not containing (product) one or more other additives or ingredients - for various end-use applications. Thus, the formulation techniques according to the embodiments of this third aspect preferably impart improved stability and / or suitability for use as a food, feed, pharmaceutical, or personal care (pre-) product.

[0155] A variety of formulation techniques are well known in the fields to which the present invention is applicable. A typical goal of such techniques is to incorporate the main desired ingredient (in this case the retinoid component) into a stabilized emulsion or suspension in various ways. One known formulation technique involves microencapsulation. Microencapsulation techniques are known and are generally described, and may include but are not limited to spray drying, microgranule techniques, coacervation, or spray chilling. Certain microencapsulation techniques are described in US8765186B2 which patent is hereby incorporated by reference in its entirety as if fully set forth herein.

[0156] In an embodiment, the method of the third aspect involves a microgranule formulation method. Thus, in an embodiment, the method according to the third aspect for preparing a food, feed, pharmaceutical, or personal care (pre-) product involves the following sub-steps associated with the formulation step (b):

[0157] (1) Dissolving the matrix component in water to produce a matrix solution;

[0158] (2) Heating the substance composition according to any one of the preceding claims, optionally preferably also heating the substance composition according to any one of the preceding claims in oil, to produce an active phase;

[0159] (3) Emulsify the active phase into the matrix solution to obtain a dispersion; and

[0160] (4) Dry the dispersion in the presence of a capture medium to obtain at least one microcapsule granule.

[0161] In the dissolution sub-step, the matrix material is typically dissolved in water to form a matrix solution. This will form the medium into which the microencapsulated active microcapsule granules will form. Any suitable matrix component can be used, such as lignosulfonate or hydrocolloid. As used herein, the term "hydrocolloid" includes gelatin, xanthan gum, acacia gum, pectin, guar gum, carob gum, alginate, cellulose, cellulose derivatives (such as carboxymethyl cellulose), and / or modified polysaccharides. As used herein, the term "modified polysaccharide" refers to a polysaccharide containing a lipophilic moiety (such as a hydrocarbon moiety having a chain length of preferably 5 to 18 carbon atoms in a straight chain). Preferably, the modified polysaccharide should be suitable for human consumption, i.e., the preferred modified polysaccharide should be GRAS (Generally Recognized as Safe) or approved for food consumption as determined by various regulatory agencies around the world. The preferred modified polysaccharide is modified food starch.

[0162] As used herein, the term "modified food starch" refers to a modified starch made by replacing starch with a hydrophobic moiety by known chemical methods. For example, starch can be treated with a cyclic dicarboxylic anhydride (such as succinic anhydride and / or glutaric anhydride) and substituted with an alkyl or alkenyl hydrocarbon group. According to certain embodiments, preferred starches include sodium octenyl succinate starch ("OSA").

[0163] OSA starch can contain additional hydrocolloids such as starch, maltodextrin, carbohydrates, gums, corn syrup, etc., and optionally any typical emulsifier (as a co-emulsifier), such as monoglycerides and diglycerides of fatty acids, polyglycerol fatty acid esters, lecithin, sorbitan monostearate, and plant fibers or sugars. OSA starch can be commercially obtained, for example, from National Starch under the trade names HiCap 100, Capsul, Capsul HS, Purity Gum 2000, UNI-PURE, NYLON VII; from Roquette Freres; from CereStar under the trade name C*EmCap, or from Tate&Lyle.

[0164] The terms "modified polysaccharide", "modified starch" and "OSA starch" further also cover modified polysaccharides / modified starches / OSA starches which have been partially hydrolysed enzymatically, for example by glycosylases (EC 3.2; see http: / / www.chem.qmul.ac.uk / iubmb / enzyme / EC3.2 / ), and modified polysaccharides / modified starches / OSA starches which have been partially hydrolysed chemically by known methods.

[0165] In other embodiments, the matrix component may comprise modified (food) starch, pectin, alginate, carrageenan, furcellaran, chitosan, maltodextrin, dextrin derivatives, cellulose and cellulose derivatives (such as cellulose acetate, methylcellulose, hydroxypropylmethylcellulose), lignosulphonates, polysaccharide gums (such as gum acacia, gum arabic, linseed gum, indian gum, tamarind gum and arabinogalactan), gelatin (bovine, fish, porcine, poultry), vegetable proteins (such as pea, soya, castor bean, cotton, potato, sweet potato, cassava, rapeseed, sunflower, sesame, linseed, safflower, lentil, nut, wheat, rice, maize, barley, rye, oats, lupin and sorghum), animal proteins (including milk protein or whey protein), lecithin, polyglycerol fatty acid esters, monoglycerol fatty acid esters, diglycerol fatty acid esters, sorbitan esters, PG esters and sugar esters (and their derivatives).

[0166] The heating sub-step involves heating the substance composition, preferably also heating the substance composition in oil, to produce an active phase. The substance composition used in this step is preferably a retinol-containing composition produced by fermentation according to any of the embodiments of the first aspect of the present invention, as described elsewhere herein, ibid.

[0167] Any suitable oil may be used, but it is highly preferred that the oil used is compatible with the substance composition into which the oil is to be incorporated. In a preferred embodiment, the oil is a triglyceride, optionally selected from vegetable oils and / or fats such as corn oil, sunflower oil, (hydrogenated) soybean oil, safflower oil, rapeseed oil, peanut oil, (hydrogenated) palm oil, palm kernel oil, cottonseed oil and / or coconut oil, including their fractionation characteristics. The triglyceride may preferably be a so-called MCT (medium-chain triglyceride), i.e. an ester of a medium-chain fatty acid (preferably a saturated fatty acid with a chain length of 6 to 12 carbon atoms) and glycerol. Preferred triglycerides are corn oil, sunflower oil, (hydrogenated) soybean oil and / or (hydrogenated) palm oil.

[0168] According to certain embodiments, it is useful to include a fat-soluble antioxidant as this will further limit the degradation and / or oxidation of the active “retinoid component” during and after the formulation process. The fat-soluble antioxidant can be incorporated at any suitable time, for example during sub-step (2) of heating the substance composition and the oil. Any suitable fat-soluble antioxidant can be employed, such as ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, tert-butyl hydroxyquinoline, ethoxyquin, and / or ascorbyl esters of fatty acids.

[0169] The amounts and ratios of the matrix component, water, substance composition, oil, and fat-soluble antioxidant as described above can be modified as needed and as understood by a person skilled in the art of the field to which the present invention pertains.

[0170] In the case of providing a matrix solution and an active phase, it becomes necessary to emulsify the active phase into the matrix solution to obtain a dispersion. This can be achieved by a variety of techniques and methods, such as the techniques and methods described by way of non-limiting example in US8765186.

[0171] The dispersion can optionally be further processed to ensure a desired droplet size or distribution, and this can be achieved by feeding it, for example, through a homogenizer. Thereafter, the dispersion is preferably pumped into one or a series of devices to remove any solvent and dry the dispersion.

[0172] The drying step can be carried out using any conventional drying method known to a person skilled in the art, which is preferably freeze-drying, spray-drying, a combination of spray-drying and fluidized bed granulation (commonly referred to as fluidized bed spray-drying or FSD), and / or a powder capture method in which the sprayed emulsion or dispersion droplets are captured in a bed of absorbent (such as starch or calcium silicate or silicic acid or calcium carbonate or mixtures thereof), followed by drying.

[0173] It is advantageous if the residual moisture content in the powder obtained by the drying sub-step is in the range of 0.5 wt% to 7.0 wt%, preferably 4 wt% to 6 wt%, based on the total weight of the material respectively. If freeze-drying is utilized, the freeze-drying is preferably carried out at a temperature of -20 °C to -50 °C for 10 hours to 48 hours. In a preferred embodiment, spray-drying is carried out on the emulsion or dispersion obtained / obtainable by the method of such embodiments of the third aspect of the present invention. In this case, it is preferred to select the spray-drying parameters as follows:

[0174] Air inlet: from about 100 °C to about 250 °C, preferably from about 150 °C to about 200 °C, more preferably from about 160 °C to about 190 °C;

[0175] Air outlet: about 45 °C to about 160 °C, preferably about 55 °C to about 110 °C, more preferably about 65 °C to about 95 °C. The solid form can be further dried and / or granulated via a variety of other known techniques.

[0176] Preferably, the drying process involves spraying the dispersion into a container containing a capture medium. The capture medium traps the dispersed particles and surrounds the dispersed particles, thereby further effectively facilitating drying. The advantage of the capture medium is that this drying can be accomplished at a lower temperature with a lower energy input compared to conventional spray drying techniques.

[0177] A preferred capture medium is corn starch, but any other suitable capture medium can be used depending on the specific nature of the active retinoid component and the desired end-use application. When the method involves the sub-step of drying a dispersion in the presence of a capture medium, the resulting product is called a microgranule. Techniques for producing microgranules are known to produce formulations with a high level of stability, optimized handling, and good dissolution characteristics.

[0178] The inventors have found that the compositions described in the embodiments of the first aspect and / or those compositions produced by the embodiments of the second aspect are particularly suitable for such processes for generating microgranules, especially because they possess excellent oxidative stability characteristics.

[0179] Another formulation technique that can be employed according to other embodiments of the third aspect of the present invention involves extrusion. Extrusion techniques are generally well known and are particularly described in WO2014083065 which is hereby incorporated by reference in its entirety as if fully set forth herein. Other exemplary publications include WO 2007 / 055815A1, WO 2021 / 163836 A1, WO 2014 / 083065 A1, WO 2017 / 005622 A1, and WO 2019 / 175326A1. The main advantage of using extrusion techniques is that highly viscous solutions can be formulated and less water can be used for dispersion, which then requires less drying. In addition, the extrusion process can be run as a continuous process. It can be found in the prior art that emulsions containing fat-soluble vitamins are extruded. US2004 / 0201116 discloses a pellet obtained by a combination of producing an emulsion using a device such as a high-pressure homogenizer and subsequent direct granulation or extrusion as a second method step.

[0180] According to an embodiment using this so-called extrusion method, the formulation step (b) of the third aspect involves the following sub-steps:

[0181] (1) Introduce the substance composition, matrix component, water, and oil according to any one of the preceding claims into an extruder having an orifice; and

[0182] (2) Extrude the substance composition, the matrix component, the water, and the oil through the orifice to produce an extrudate.

[0183] The introduction sub-step (1) requires the introduction of a composition, preferably any fermented retinoid-containing composition and / or any such composition produced via any embodiment of the second aspect of the present invention, among the fermented retinoid-containing compositions according to any embodiment of the first aspect of the present invention, as well as a matrix component, an oil, and water. The matrix component and the oil can be selected from any suitable type, including those described above in connection with the microgranule technology embodiments of the third aspect. As described above with respect to other microencapsulation techniques, a water-in-oil / matrix emulsion or dispersion should be formed between the components.

[0184] The emulsion or dispersion can be formed as a pre-mixed active phase before being incorporated into the extruder, or alternatively - as described in WO2014083065 - formed inside the extruder device itself. Thus, the introduction of the composition or "active ingredient", oil, water, and matrix can be carried out in four different steps at four different positions as deemed appropriate, more strictly, or at most. The inventors have surprisingly found that the fermented retinoid-containing compositions according to the first aspect and / or those compositions produced via the method according to the second aspect are particularly suitable for the extrusion method, in which the emulsion is formed inside the extruder itself. Without wishing to be bound by any theory, the inventors speculate that this may be due to the excellent oxidative stability of such compositions.

[0185] In sub-step (2), the introduced materials pass through the extruder and are finally extruded through the orifice to obtain an extrudate. In a non-limiting embodiment, the extruder device includes an extrusion die having a circular orifice for the exit of the material. Behind the die, the device typically includes one or more feeders for supplying the material into the barrel, where one, two, or more screws driven by a mechanical drive (e.g., an electric, hydraulic, or pneumatic motor) mix the material, convey the material towards the die, and build pressure. Optionally, means for heating and / or cooling the material can be provided at a certain point in the barrel. The socket for holding the die can also be heated or cooled. When in operation, the extruded material exits the orifice as a strand having a specific cross-section. The emulsion or suspension containing the substance composition, matrix component, water, and oil remains viscous during extrusion and solidifies by cooling and / or drying after leaving the extrusion die.

[0186] After extrusion, the following sub-steps are also preferably incorporated: (3) cutting the extrudate into discrete particles, and (4) optionally, drying the discrete particles. For the avoidance of doubt, these steps need not be carried out sequentially and may be carried out simultaneously; indeed, a certain amount of drying preferably occurs not only after cutting, but also preferably before and during such processes.

[0187] In a preferred embodiment, at the outlet and / or orifice of the extrusion die, a cutter cuts pellets from the extrudate. In an embodiment, a lateral flow of conveying fluid (usually conveying air) carries the pellets away from the die; however, although the conveying fluid has a cooling and drying effect, the mass is usually still sticky and tacky, especially in the core of the strand. This can cause blockage of machine parts, especially the cutter and the extrusion die, and is not conducive to process stability and maintenance frequency. It can also cause agglomeration of the product particles themselves and is not conducive to product quality. Depending on the type of mass and the shape and size of the extrudate, adjusting the temperature and flow rate of the conveying air or cooling the blades of the cutter by a separate cooling air stream may or may not always satisfactorily solve this problem.

[0188] Accordingly, the drying step may further comprise means for providing an additional vertical cooling air stream exiting the outlet to increase the cooling and drying rate of the extrudate, particularly at and around the core of the extrudate, compared to cooling and drying by transporting separate air. Further, the step has an additional cooling effect on the blades of the cutter when compared to cooling only the air exiting the outlet.

[0189] These effects of cooling the air exiting such an outlet are particularly advantageous when extruding an oil-in-water emulsion containing a fat-soluble nutrient or a pharmaceutically active agent dissolved in oil particles of an emulsion. The emulsion typically contains a thickening or gelling agent, which makes them very viscous when exiting the die at high temperature, and the direct flow of vertical cooling air onto the surface of the exiting material strand reduces the stickiness and the tendency for blockage of the apparatus. Accordingly, in an embodiment, the formulation step (b) further comprises the step of directing a cooling fluid stream to the orifice and the extrudate. In an embodiment, this directing step is carried out such that the cooling fluid is configured to flow along a cooling flow axis and the extrudate is configured to be extruded through an exit axis, wherein the cooling flow axis and the exit axis are substantially anti-parallel and / or substantially collinear.

[0190] A fourth aspect of the present invention is a microcapsule granule or an extrudate produced by a method according to any embodiment in the embodiments of the third aspect of the present invention, and / or a microcapsule granule or an extrudate incorporated with a substance composition according to any embodiment in the embodiments of the first aspect of the present invention, and / or a microcapsule granule or an extrudate made by a method according to any embodiment in the embodiments of the second aspect of the present invention.

[0191] A fifth aspect of the present invention is a food, feed, medicine or personal care product, which comprises any one of the following: an extrudate and / or a microcapsule granule according to the fourth aspect; and / or an extrudate and / or a microcapsule granule made by a method according to any embodiment in the embodiments of the third aspect; and / or an extrudate and / or a microcapsule granule containing a substance composition according to any embodiment in the embodiments of the first aspect; and / or an extrudate and / or a microcapsule granule made by a method according to any method in the embodiments of the second aspect.

[0192] Especially if used in a personal care product, the composition according to the first aspect or the product according to the fifth aspect incorporating the composition advantageously has antimicrobial activity. As used herein, the term "antimicrobial activity" or "antimicrobial effect" preferably refers to the ability to inhibit and / or eliminate the growth of skin microorganisms (especially Propionibacterium acnes, Corynebacterium xerosis and / or Malassezia, preferably Malassezia furfur) in a given sample or in a human or animal in need, compared to an inoculum or a control, as outlined in the examples. The terms "eliminate" and "kill" may be used interchangeably herein. The term "growth" of skin microorganisms as used herein and in combination therewith refers to the undesired or unhealthy growth of microorganisms as defined herein, resulting in an increase in microbial cells on the skin compared to a balanced and healthy skin microbiota.

[0193] Due to the antimicrobial activity against skin microorganisms (such as Propionibacterium acnes, Corynebacterium xerosis and / or Malassezia, especially Malassezia furfur), the composition according to the first aspect and / or the product according to the fifth aspect incorporating the composition can be applied to treat, prevent and / or alleviate the symptoms of adverse skin conditions associated with overpopulation of said microorganisms, such as acne control applications (Propionibacterium acnes), deodorant applications (Corynebacterium xerosis) and hair care, especially anti-dandruff applications (Malassezia, preferably Malassezia furfur).

[0194] For example, the above-mentioned antimicrobial effect can be used for microbiota balance, for example when applied to the outer surface of the human or animal body.

[0195] Thus, in another embodiment, the composition according to the first aspect and / or the product according to the fifth aspect incorporated into said composition can be particularly used as an antimicrobial compound in cosmetic or pharmaceutical products for controlling / reducing acne, in particular for inhibiting the overpopulation of Propionibacterium acnes on the skin, as a component of a deodorant, in particular for inhibiting the overpopulation of Corynebacterium xerosis that causes malodor when sweating, or for controlling / reducing dandruff, in particular for inhibiting the overpopulation of the genus Malassezia, preferably Malassezia furfur.

[0196] However, said antibacterial effect can also be used for preventing and / or treating diseases related to skin microbiota dysbiosis or imbalance, which is associated with an increase (or overpopulation) / growth in the number of Propionibacterium acnes, Corynebacterium xerosis and / or Malassezia, in particular Malassezia furfur.

[0197] It is well-known that the composition according to the first aspect of the present invention and / or the product according to the fifth aspect incorporated into said composition can be used for both cosmetic and pharmaceutical purposes.

[0198] Drug applications can be envisaged, for example, for treating, preventing and / or alleviating any disorders and diseases associated with said microorganisms (such as in particular Propionibacterium acnes and / or Malassezia, preferably Malassezia furfur) in a human (such as a patient) or an animal in need, such as for treating, preventing and / or alleviating the symptoms of pityriasis versicolor, dandruff formation, seborrheic dermatitis, atopic dermatitis, psoriasis and acne.

[0199] Cosmetic applications can be envisaged if the application aims to maintain and / or enhance the beauty and / or youth of a human, especially when it concerns the appearance of tissues or skin. The preferred cosmetic (non-therapeutic) applications according to the present invention cover treating, preventing and / or alleviating the symptoms of skin itching, maintaining skin homeostasis, providing microbiota balance and reducing the formation of malodor caused by sweat.

[0200] In order to utilize the antimicrobial activity against Propionibacterium acnes, Corynebacterium xerosis and / or Malassezia, preferably Malassezia furfur, the composition according to the first aspect and / or the product according to the fifth aspect comprising said composition can be used in a variety of applications, such as cosmetic or pharmaceutical compositions.

[0201] Thus, in another embodiment, the composition according to the invention is a cosmetic or pharmaceutical composition further comprising a cosmetic or pharmaceutically acceptable carrier. The term "cosmetic or pharmaceutically acceptable carrier" refers to all carriers and / or excipients and / or diluents conventionally used in cosmetic compositions or pharmaceutical compositions. As used herein, it can be understood as a physiologically acceptable medium, i.e., a medium compatible with the intended use, for example, a medium compatible with keratinous substances (such as skin, mucous membranes, and keratin fibers).

[0202] As used in this application, the term "cosmetic composition" or "cosmetic product" refers to a composition as defined under the heading "Kosmetika" in Lexikon Chemie, 10th Edition, 1997, Georg Thieme Verlag Stuttgart, New York, and to cosmetic compositions as disclosed in A. Domsch, "Cosmetic Compositions", Verlag für chemische Industrie (edited by H. Ziolkowsky), 4th Edition, 1992, and refers to a product / composition for treating, caring for, or improving the appearance of the skin and / or scalp.

[0203] As used herein, the term "pharmaceutical composition" or "pharmaceutical product" refers to a composition for treating, preventing, and / or alleviating the symptoms of a disease and / or disorder.

[0204] Thus, in another advantageous embodiment, the cosmetic or pharmaceutical composition / product according to the invention is an anti-acne composition / product, which comprises the composition according to the first aspect and / or the product according to the fifth aspect incorporated into the composition, and the composition and / or product are potentially suitable for killing or significantly inhibiting the growth of Propionibacterium acnes. Particularly suitable anti-acne compositions are creams, lotions, etc., preferably in the form of an emulsion, such as an oil-in-water (O / W) emulsion as disclosed herein.

[0205] It is also advantageous according to the invention to use the composition according to the first aspect having all the definitions and preferences given herein and / or the product according to the fifth aspect incorporating the composition as an active compound in an anti-dandruff preparation, because the composition and / or product have an antimicrobial effect against the genus Malassezia, preferably Malassezia furfur, even at a very low concentration of less than about 0.3% by weight.

[0206] Thus, in another advantageous embodiment, the cosmetic or pharmaceutical composition / product according to the invention is an anti-dandruff composition according to the fifth aspect, comprising, based on the total weight of the composition, from 0.1% to 0.3% by weight of the composition, since these compositions are particularly suitable for killing or significantly inhibiting the growth of Malassezia spp., preferably Malassezia furfur. Particularly suitable anti-dandruff compositions are shampoos and hair tonics.

[0207] The cosmetic or pharmaceutical composition / product as disclosed herein is preferably an aqueous composition, i.e., a composition comprising water.

[0208] Furthermore, it is advantageous that the water content in the cosmetic or pharmaceutical composition / product according to the invention is, based on the total weight of the composition, at least about 30% by weight, preferably at least about 40%, 45%, 50%, 60%, 70%, 80%, 90% by weight, for example in the range of 30% to 90% by weight, such as 40% to 90%, 45% to 90% or 50% to 90% by weight. Further suitable ranges are 30% to 75%, 30% to 70%, 30% to 60% and 40% to 60% by weight.

[0209] In a specific embodiment, the product according to the fifth aspect is a cosmetic composition intended for topical application to mammalian keratinous tissues, such as in particular human / animal skin or human / animal scalp. Such compositions are also referred to as dermatological compositions. Thus, preferably in certain embodiments of the invention, the cosmetic composition is a topical cosmetic (i.e., dermatological) composition / product having all the definitions and preferences as given herein.

[0210] The topical cosmetic composition / product according to the invention can be a leave-on or rinse-off composition and includes any cosmetic product applied to the human body mainly for improving appearance, cleaning, odor control or general aesthetics. Preferably, the cosmetic composition of the invention is a leave-on composition.

[0211] It is well known that the cosmetic composition / product according to the invention intended for topical application comprises a physiologically acceptable medium, i.e., a medium compatible with keratinous substances (such as skin, mucous membranes and keratin fibers). Specifically, the physiologically acceptable medium is a cosmetically acceptable carrier. In all embodiments of the invention, it is preferred that the carrier comprises water.

[0212] The term "cosmetically acceptable carrier" (also referred to herein as carrier) refers to all vehicles / carriers conventionally used in cosmetic compositions, i.e., vehicles / carriers suitable for topical application to the horny tissue, having good aesthetic properties, compatible with the active substances present in the composition / product, and not causing any unreasonable safety or toxicity problems. Such carriers are well-known to those of ordinary skill in the art and can include one or more compatible liquid or solid filler diluents, excipients, additives, or vehicles suitable for application to the skin.

[0213] The exact amount of the carrier will depend on the actual levels of the active ingredient and any other optional ingredients (e.g., other active ingredients) that those of ordinary skill in the art would classify as different from the carrier.

[0214] The cosmetic composition according to the fifth aspect of the present invention preferably contains, based on the total weight of the composition, 50% to 99.995% by weight of the composition, e.g., 50% to 99.95%, more preferably 60% to 99.995%, e.g., 60% to 99.95%, still more preferably 75% to 99%, and most preferably 80% to 98%, e.g., 90% to 98% of the carrier.

[0215] The cosmetic composition / product according to the fifth aspect of the present invention can be in the form of a liquid, lotion, thickened lotion, gel, cream, emulsion, ointment, paste, powder, cosmetic, or solid stick, and can optionally be packaged as an aerosol and can be provided in the form of a mousse (e.g., aerosol mousse), foam or spray foam, spray, stick.

[0216] Preferably, the cosmetic composition / product according to the fifth aspect of the present invention is in the form of a lotion, cream, gel, and tonic. These product forms can be used for a variety of applications, including but not limited to hand creams and body lotions, facial moisturizers, anti-aging products, cosmetics including foundations, etc. Any additional components required to formulate such products vary with the product type and can be routinely selected by those skilled in the art.

[0217] If the cosmetic composition according to the fifth aspect of the present invention is formulated as an aerosol and applied to the skin as a spray product, a propellant is added to the composition.

[0218] The cosmetic composition / product according to the fifth aspect of the present invention can be prepared by conventional methods in the art, e.g., by admixing a mixture or composition comprising a mixture of cis / trans isomers of a retinoid as defined herein having a cis / trans ratio of less than 0.01 with all the definitions and preferences given herein with a cosmetically acceptable carrier.

[0219] The cosmetic composition / product may comprise additional ingredients which may form part of the carrier. Such ingredients are in particular surfactants, emulsifiers, thickeners and oils. Such suitable surfactants, emulsifiers, thickeners and oils are well known to the person skilled in the art.

[0220] The cosmetic composition / product according to the fifth aspect of the invention (comprising a carrier) may comprise further conventional (cosmetic) adjuvants and additives such as preservatives / antioxidants, fatty substances / oils, water, organic solvents, silicones, thickeners, emollients, emulsifiers, defoamers, aesthetic components (such as fragrances), surfactants, fillers, anionic polymers, cationic polymers, nonionic polymers or amphoteric polymers or mixtures thereof, propellants, acidifying or alkalizing agents, dyes, colorants / staining agents, abrasives, absorbents, chelating agents and / or polyvalent chelating agents, essential oils, skin sensates, astringents, pigments, or any other ingredients customarily formulated in such compositions.

[0221] Unless otherwise stated, the excipients, additives, diluents, etc. mentioned below are applicable to the compositions according to the invention. The necessary amounts of cosmetic and dermatological adjuvants and additives can be readily determined by the person skilled in the art based on the desired product.

[0222] Additional ingredients can be added to the oil phase, the water phase or separately as appropriate. The person skilled in the art can readily adapt the mode of addition.

[0223] Examples of suitable cosmetic surfactants, emulsifiers, thickeners, oils, excipients, diluents, adjuvants, additives and active ingredients commonly used in the skin care industry for the cosmetic compositions according to the invention are described, for example, in the International Cosmetic Ingredient Dictionary & Handbook by Personal Care available via the online INFO BASE (http: / / online.personalcarecouncil.org / jsp / Home.jsp) provided by the Personal Care Products Council (http: / / www.personalcarecouncil.org / ), but are not limited thereto.

[0224] In some cases, the cosmetic active ingredients available herein can provide more than one benefit or act via more than one mode of action.

[0225] Of course, those skilled in the art will take care to select the above optional additional components, adjuvants, diluents and additives and / or their amounts such that the advantageous properties essentially associated with the combination according to the invention are not or are substantially not adversely affected by one or more of the envisaged additions.

[0226] The cosmetic composition / product according to the invention is in particular a skin care product, a functional product and / or a hair care product, such as most particularly a skin care product or a hair care product.

[0227] Examples of skin care preparations are in particular photoprotective preparations (sun protection preparations), anti-aging preparations, preparations for treating photoaging, body oils, body lotions, body gels, care creams, skin care ointments, moisturizing preparations (such as moisturizing gels or moisturizing sprays), facial and / or body moisturizers, and skin brightening preparations.

[0228] Examples of functional preparations are cosmetic compositions containing active ingredients, such as but not limited to hormonal products, vitamin products, plant extract products, anti-aging products, and / or antimicrobial (antibacterial or antifungal) products.

[0229] Examples of hair care products suitable according to the invention and which may be mentioned are shampoos, conditioners (also known as hair rinses), hair styling compositions, hair tonics, hair regeneration compositions, hair lotions, perm lotions, hair sprays, hair creams, hair gels, hair oils, hair pomades or hair brilliantines. These products are thus always products which are applied to the hair and scalp for a shorter or longer time depending on their actual intended use.

[0230] Preferably, in an embodiment of the invention, the skin / functional and / or hair care preparation is a deodorant, antiperspirant, antidandruff or anti-acne composition comprising the composition according to the first aspect of the invention.

[0231] In a preferred embodiment, the cosmetic product / composition according to the invention is in the form of an emulsion and / or a gel. More preferably, the cosmetic composition is an emulsion containing an oil phase and an aqueous phase, such as in particular O / W, W / O, Si / W, W / Si, O / W / O, W / O / W multiple or Pickering emulsions, PIT emulsions, nanoemulsions, microemulsions, multiple emulsions (such as O / W / O type or W / O / W type).

[0232] The amount of the oil phase (i.e., the phase containing all oils and fats, including polar oils) present in such emulsions (such as especially O / W, W / O, Si / W, W / Si, O / W / O, W / O / W multiple or Pickering emulsions) is, based on the total weight of the composition, preferably at least about 10% by weight, for example in the range of 10% to 60% by weight, preferably in the range of 15% to 50% by weight, and most preferably in the range of 15% to 40% by weight.

[0233] The oil phase according to the invention preferably comprises an oil selected from: butylene glycol dicaprylate / dicaprate, polydimethylsiloxane, propylene glycol dicaprylate / dicaprate, diisooctyl ether, C 12-15 -alkyl benzoates, C 18-38 -fatty acid triglycerides, dibutyl adipate, cyclomethicone, 2-phenylethyl benzoate, isopropyl lauroyl sarcosinate, caprylic / capric triglyceride, and mixtures thereof.

[0234] The amount of the aqueous phase present in such emulsions is, based on the total weight of the composition, preferably at least about 20% by weight, for example in the range of 20% to 90% by weight, preferably in the range of 30% to 80% by weight, and most preferably in the range of 30% to 70% by weight.

[0235] Advantageously, in all emulsions of the invention, the ratio of the oil phase to the aqueous phase is selected from the range of 40:60 to 30:70.

[0236] In a particularly advantageous embodiment, the cosmetic composition according to the fifth aspect of the invention is in the form of an oil-in-water (O / W) emulsion, said O / W emulsion comprising an oil phase dispersed in an aqueous phase in the presence of an O / W emulsifier. The preparation of such O / W emulsions is well known to those skilled in the art.

[0237] If the cosmetic composition according to the fifth aspect of the invention is an O / W emulsion, it advantageously comprises at least one O / W or Si / W type emulsifier selected from the following list: glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, stearates, polyglyceryl-3-methylglucose distearate. Other suitable emulsifiers are phosphate esters and their salts, such as cetyl phosphate (e.g., A) from DSM Nutritional Products Ltd., diethanolamine cetyl phosphate (e.g., DEA) from DSM Nutritional Products Ltd., potassium cetyl phosphate (e.g., K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphates, and mixtures thereof. Other suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose poly stearate, and hydrated polyisobutene. In addition, one or more synthetic polymers can be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C10-30 alkyl acrylate crosslinked polymer, and mixtures thereof.

[0238] The at least one O / W or Si / W type emulsifier is preferably used in an amount in the range of 0.5% to 10% by weight, particularly in the range of 0.5% to 6% by weight, more particularly in the range of 0.5% to 5% by weight, and most particularly in the range of 1% to 4% by weight, based on the total weight of the cosmetic composition.

[0239] Particularly suitable O / W type emulsifiers for use in the cosmetic composition according to the fifth aspect include phosphate ester emulsifiers, such as advantageously C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, cetearyl alcohol polyether-2 phosphate, cetearyl alcohol polyether-5 phosphate, cetyl alcohol polyether-8 phosphate, cetyl alcohol polyether-10 phosphate, cetyl phosphate, C6-10 alkanol polyether-4 phosphate, C12-15 alkanol polyether-2 phosphate, C12-15 alkanol polyether-3 phosphate, DEA-cetearyl alcohol polyether-2 phosphate, DEA-cetyl phosphate, DEA-oleyl alcohol polyether-3 phosphate, potassium cetyl phosphate, decyl alcohol polyether-4 phosphate, decyl alcohol polyether-6 phosphate, and trilauryl alcohol polyether-4 phosphate.

[0240] A particularly suitable O / W emulsifier for use in the cosmetic composition according to the fifth aspect is potassium cetyl phosphate, which can be commercially obtained, for example, from DSM Nutritional Products Ltd Kaiseraugst as K.

[0241] Another class of particularly suitable O / W emulsifiers is nonionic self-emulsifying systems derived from olive oil, such as those sold under the trade name OLIVEM 1000 and known as (INCI name) cetyl olive esters and sorbitan olivate (chemical composition: sorbitan esters and cetearyl esters of olive oil fatty acids).

[0242] In a specific embodiment according to the fifth aspect, the present invention relates to a cosmetic composition / product in the form of an O / W emulsion having all the definitions and preferences given herein, said O / W emulsion comprising an oil phase dispersed in an aqueous phase in the presence of an O / W emulsifier, wherein the O / W emulsifier is potassium cetyl phosphate. The amount of the oil phase in such an O / W emulsion is based on the total weight of the composition, preferably at least about 10% by weight, more preferably in the range of 10% to 60% by weight, most preferably in the range of 15% to 50% by weight, for example in the range of 15% to 40% by weight.

[0243] Preferably, the cosmetic composition according to the fifth aspect of the present invention further comprises at least one fatty alcohol (co-emulsifier), such as in particular cetyl alcohol, cetearyl alcohol and / or behenyl alcohol. The total amount of one or more fatty alcohols in the topical composition according to the present invention is preferably selected from the range of about 0.1% to about 10.0% by weight, in particular from the range of about 0.5% to 6.0% by weight, relative to the total weight of the topical composition.

[0244] Preferably, the topical composition according to the fifth aspect comprises a thickening agent, especially if the topical composition is in the form of an emulsion, to help make the consistency of the product appropriate. Preferred thickening agents are aluminium silicate, xanthan gum, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyacrylates such as carbomers (e.g. 980, 981, 1382, 2984, 5984) or mixtures thereof. Further preferred thickening agents include acrylate / C 10-30 alkyl acrylate copolymers (such as Pemulen produced by NOVEON TM TR-1, Pemulen TM TR12, 1328) and AVC (INCI: ammonium acryloyldimethyltaurate / VP copolymer).

[0245] The cosmetic composition according to the fifth aspect advantageously comprises a preservative. When present, the preservative is used in an amount of preferably 0.1% to 2% by weight, more preferably 0.5% to 1.5% by weight, based on the total weight of the composition.

[0246] The pH of the cosmetic composition according to the fifth aspect is in the range of 3 to 10, preferably in the range of 4 to 8, and most preferably in the range of pH 4 to 7.5, for example in the range of 5 to 6.5. It can be adjusted by methods known to those skilled in the art, for example by using an acid (such as citric acid) or a base (such as sodium hydroxide (for example as an aqueous solution), triethanolamine (TEA Care), tromethamine (Trizma base), and aminomethylpropanol (AMP-Ultra PC2000)) to adjust the pH according to standard methods in the art.

[0247] The amount of the cosmetic composition to be applied to the skin is not critical and can be easily adjusted by those skilled in the art. Preferably, the amount is selected from 0.1 mg / cm 2 skin to 3 mg / cm 2 skin, for example preferably in the range of 0.1 mg / cm 2 skin to 2 mg / cm 2 skin, and most preferably in the range of 0.5 mg / cm 2 skin to 2 mg / cm 2 skin.

[0248] The fermentatively produced retinoid-containing composition of the present invention (and associated foods, feeds, pharmaceuticals, and / or personal care products) can be formulated by selecting the components specified above herein, and can be further easily formulated by following the formulation guidelines herein and by extrapolating from the general methods employed in the embodiments described below. Such embodiments below further illustrate the present invention, but of course should not limit the scope of the present invention in any way.

[0249] Examples

[0250] These examples illustrate embodiments of the present invention. Table 1 describes the characterization of various retinoid-containing substance compositions as used in the examples of the present invention. Table 2 indicates the results of certain thermal stability performance tests conducted on the examples characterized as in Table 1. Meanwhile, Table 3 demonstrates the biobased content of exemplary fermentatively produced retinoid-containing substance compositions. Finally, Table 4 describes the antimicrobial performance tests conducted on other retinoid-containing substance compositions tuned to have different isomer ratios.

[0251] General methods and strains

[0252] All basic molecular biology and DNA manipulation procedures described herein were generally carried out according to Sambrook et al. (eds.), Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press: New York (1989) or Ausubel et al. (eds.) Current Protocols in Molecular Biology. Wiley: New York (1998). All genetic manipulations exemplified were carried out in Yarrowia lipolytica.

[0253] Oscillating plate assay. Typically, 10 μl of freshly growing Yarrowia was inoculated into 200 μl of 0.075% yeast extract, 0.25% peptone (0.25X YP) and overlaid with 200 μl of Drakeol 5 (Penreco, Karns City, PA, USA), mineral oil, silicone oil or corn oil containing 2% oleic acid or 2% glucose as a carbon source. Clonal isolates of the transformants were grown for 4 days in YPD medium with one of the overlays shown previously in 24-well plates (Multitron, 30 °C, 800 RPM). The overlay fractions were removed from the shake flask wells and analyzed by HPLC on a normal phase column using a photodiode array detector.

[0254] DNA transformation.Transform the strain by overnight growth on YPD plate medium. Scrape 50 μl of cells from the plate and then transform by incubating in 500 μl containing 1 μg of transforming DNA (usually linear DNA for integrative transformation), 40% PEG 3550 MW, 100 mM lithium acetate, 50 mM dithiothreitol, 5 mM Tris-Cl pH 8.0, 0.5 mM EDTA at 40 °C for 60 minutes, followed by direct plating onto selective medium or, in the case of selection with a dominant antibiotic marker, growing the cells on YPD liquid medium at 30 °C for 4 hours and then plating onto selective medium. Nourseothricin (Nat) selection is carried out on YPD medium containing 100 μg / mL nourseothricin, and hygromycin (Hyg) selection is performed on YPD containing 100 μg / mL hygromycin. URA3 marker recycling is carried out using 5-fluoroorotic acid (FOA). The episomal hygromycin resistance marker (Hyg) plasmid is cured by passage on non-selective medium, and Hyg-sensitive colonies are identified by replica plating colonies from non-selective medium onto medium containing hygromycin (100 μg / mL). The hygromycin resistance marker of the hygromycin-labeled DNA for integration is recovered using standard methods for Cre recombinase expression and identification of sensitive colonies by replica inoculation.

[0255] Plasmid list. The plasmids, strains, and nucleotide sequences used are listed below and in Table 5 herein. Generally, all unmodified sequences mentioned herein are the same as the accession sequences of the reference strain CLIB122 in the database (Dujon B et al., Nature. 2004 Jul 1;430(6995):35-44).

[0256] Preparation and fermentation conditions of retinol-producing Yarrowia lipolytica strains

[0257] Using the method described in WO2022090548, the strain ML18743 described in WO2022090548 was successively transformed with plasmid MB8203 digested with HindIII+XbaI and plasmid MB9894 digested with HindIII+XbaI (as described in the following table) to generate strain ML18743+MB8203+MB9894. This strain was transformed with plasmid MB9523 digested with SfiI to generate the new strain ML18934. Then the strain ML18934 was transformed with plasmid MB7270 digested with SfiI to generate the new strain ML19284. This strain was made ku70- by CRISPR mutagenesis with plasmid MB9282. For this strain, DNA41 and DNA53 were successively integrated by nuclease-guided integration using homologous recombination to generate the new strain ML19649. Using Isopar M as the second phase, ethanol feed was used to ferment strains ML18934, ML19284, and ML19649, as described in WO2022090548 and further described below and in the sequence listing of Table 5.

[0258]

[0259]

[0260] Then the strains produced as described above were used in the fermentation process to produce Examples 1 to 4 further described below.

[0261] Fermentation

[0262] Fermentation product used in Example 1

[0263] Production reactor: New Brunswick Bioflo 610.

[0264] Seed train: Shake flasks (250 ml) and New Brunswick Bioflo 310

[0265] Strain: ML18934

[0266] Medium: 6.13 g / l of Tastone-154, 1.96 g / l of MgSO4·7H2O, 0.2 g / l of NaCl, 0.33 g / l of CaCl·2H2O, 8.18 g / l of (NH4)2SO4, 8.47 g / l of KH2PO4, 0.2 g / l of thiamine, 8.13 g / l of DF204 antifoam, trace metals, 50 g / l of glucose, 9.86 g / l of ethanol, and 197.5 g / l of Isopar M

[0267] Seed medium:

[0268] · Flask: 30 g / l of Tastone-154, 22 g / l of glucose, 0.5 g / l of Basildon antifoam

[0269] · Bioreactor: 30 g / l of Tastone-154, 70 g / l of glucose, 10 g / l of Basildon antifoam

[0270] Batch volume 45 kg (including inoculum)

[0271] Fermentation time: 168 h

[0272] Feed: 6N NH4OH, ethanol (200 proof), DF204 antifoam

[0273] Process description: The batch phase ends when the initial glucose and ethanol are depleted. The ethanol feed rate is ramped down to 20% DO. The DO is controlled at 20% by agitation, air flow, and feed rate. The pH is controlled at 5.5 with NH4OH.

[0274] Fermentation product used in Example 2

[0275] Production reactor: New Brunswick Bioflo 610.

[0276] Seed train: Shake flask (250 ml) and New Brunswick Bioflo 310

[0277] Strain: ML19284

[0278] Medium: 1.96 g / l of MgSO4 7H2O, 0.2 g / l of NaCl, 8 g / l of (NH4)2SO4, 16 g / l of KH2PO4, 0.8 g / l of thiamine, 5 g / l of DF204 antifoam, 50 g / l of glucose, 9.86 g / l of ethanol, and 296 g / l of Isopar M Trace metals: 656 mg / l of citric acid, 58.8 mg / l of FeSO4·7H2O, 6.3 mg / l of CuSO4·5H2O, 9.45 mg / l of MnSO4·1H2O, 33.2 mg / l of ZnSO4·7H2O, 47.3 mg / l of CaCl2·2H2O

[0279] Seed medium:

[0280] · Flask: 30 g / l of Tastone-154, 22 g / l of glucose, 0.5 g / l of Basildon antifoam

[0281] · Bioreactor: 30 g / l Tastone-154, 70 g / l glucose, 10 g / l Basildon antifoamBatch volume 40 kg (including inoculum)

[0282] Fermentation time: 260 h

[0283] Feed: 6N NH4OH, ethanol (200 proof), DF204 antifoam

[0284] Process description: The batch phase ends when the initial glucose and ethanol are depleted. The ethanol feed is ramped down at a fixed rate to 20% DO. The DO is controlled at 20% by agitation, air flow, and feed rate. The pH is controlled at 5.5 with NH4OH.

[0285] Fermentation product used in Example 3

[0286] Production reactor: New Brunswick Bioflo 610.

[0287] Seed train: Shake flasks (250 ml) and New Brunswick Bioflo 310

[0288] Strain: ML19649

[0289] Medium: 1.96 g / l MgSO4·7H2O, 0.2 g / l NaCl, 8 g / l (NH4)2SO4, 16 g / l KH2PO4, 0.8 g / l thiamine, 5 g / l DF204 antifoam, 50 g / l glucose, 9.86 g / l ethanol, and 296 g / l Isopar MTrace metals: 656 mg / l citric acid, 58.8 mg / l FeSO4·7H2O, 6.3 mg / l CuSO4·5H2O, 9.45 mg / l MnSO4·1H2O, 33.2 mg / l ZnSO4·7H2O, 47.3 mg / l CaCl2·2H2O

[0290] Seed medium:

[0291] · Flasks: 30 g / l Tastone-154, 22 g / l glucose, 0.5 g / l Basildon antifoam

[0292] · Bioreactor: 30 g / l Tastone-154, 70 g / l glucose, 10 g / l Basildon antifoam

[0293] Batch volume 40 kg (including inoculum)

[0294] Fermentation time: 260 h

[0295] Feed: 6N NH4OH, ethanol (200 proof), DF204 antifoam

[0296] Process description: The batch phase ends when the initial glucose and ethanol are depleted. The ethanol feed rate is ramped down at a fixed rate to 20% DO. The DO is controlled at 20% by agitation, air flow, and feed rate. The pH is controlled at 5.5 with NH4OH.

[0297] Fermentation product used in Example 4

[0298] Production reactor: New Brunswick Bioflo 610.

[0299] Seed train: shake flasks (250 ml) and New Brunswick Bioflo 310

[0300] Strain: ML18934

[0301] Medium: 6.13 g / l of Tastone-154, 1.96 g / l of MgSO4·7H2O, 0.2 g / l of NaCl, 0.33 g / l of CaCl·2H2O, 8.18 g / l of (NH4)2SO4, 8.47 g / l of KH2PO4, 0.2 g / l of thiamine, 8.13 g / l of DF204 antifoam, trace metals, 50 g / l of glucose, 9.86 g / l of ethanol, and 197.5 g / l of Isopar M

[0302] Seed medium:

[0303] · Flasks: 30 g / l of Tastone-154, 22 g / l of glucose, 0.5 g / l of Basildon antifoam

[0304] · Bioreactor: 30 g / l of Tastone-154, 70 g / l of glucose, 10 g / l of Basildon antifoam

[0305] Batch volume 45 kg (including inoculum)

[0306] Fermentation time: 168 h

[0307] Feed: 6N NH4OH, ethanol (200 proof), DF304 antifoam

[0308] Process description: The batch phase ends when the initial glucose and ethanol are depleted. The ethanol feed rate is ramped down at a fixed rate to 20% DO. The DO is controlled at 20% by agitation, air flow, and feed rate. The pH is controlled at 5.5 with NH4OH.

[0309] Note: Fermentation was tested at high dco2 concentrations. Contamination was detected.

[0310] Creation of DSP and dry crystals

[0311] Each of Examples 1 to 4 was prepared in dry crystal form via the following method for subsequent characterization and performance testing. First, each of the above fermentation products (each containing retinyl acetate as the retinoid component) was provided in a laboratory-scale short-path evaporator (0.03 m 2 ) at an absolute pressure of about 1 mbar and a jacket temperature of 80 °C at the light phase concentration from centrifugation to achieve a retinyl acetate fraction of about 40 - 45 wt% in the residue. Next, the concentrated residue was mixed with absolute ethanol to obtain a solution containing 45 - 47 wt% ethanol at 20 °C. Then this solution was cooled to 14 °C with stirring in a 250 ml double-jacketed reactor, at which point seeds were added and the temperature was maintained at 14 °C for an additional hour. Subsequently, the reactor was cooled to -20 °C at a cooling ramp of 5 °C / h and held at -20 °C for approximately 16 hours. The resulting suspension was filtered through a Buchner vacuum funnel, pre-cooled at -20 °C, and washed twice with cold ethanol (-20 °C) to obtain wet crystals. These crystals were finally dried in a vacuum drying oven at room temperature and reduced pressure to remove any residual ethanol, thereby obtaining dry crystals.

[0312] Preparation of Example 5

[0313] Sample 5 was provided as dry retinyl acetate crystals produced via chemical synthesis, as readily available from DSM Nutritional Products AG, Kaiseraugst, Switzerland. This was used herein as a control representing a non-fermentatively produced retinoid-containing composition.

[0314] Preparation of Example 6

[0315] Example 6 is a material composition in crystalline form, consisting mainly of (i.e., >80 wt%) retinyl acetate and its fermentation residues, which retinyl acetate and its fermentation residues were generally produced by fermentation according to the same techniques and methods as those associated with the preparation of each of Examples 1 to 4 supra. Notably, the same ethanol used as a carbon source in the fermentation of each of Examples 1 to 4 was also used during the fermentation process resulting in the production of Example 6.

[0316] Since the same carbon source is used during fermentation in fact, it can be concluded that the biobased characteristics of Example 6 also represent the biobased characteristics of Examples 1 to 4.

[0317] Preparation of Examples 7 to 11

[0318] The compositions utilized in Examples 7 to 11 were prepared according to standard techniques in the fields to which the present invention is applicable and are further described below. A retinoid mixture containing retinyl acetate as defined herein can be produced as described in WO2022090549 (Example 1). The samples were controlled as much as possible to ensure that only the cis / trans isomer ratios of the retinoid components of the respective sample series (i.e., 7 to 9 and 10 to 11) would vary. The cis / trans ratios and specific properties of the retinoid components of the individual samples are indicated in Table 4 below.

[0319] Sample Characterization

[0320] Retinoid quantification: Retinoid analysis was performed using the C4 reversed-phase retinoid method (see below). The sum of all added intermediates gives the total amount of retinoid.

[0321] C4 reverse - phase chromatography. To accurately determine discrete retinoids, a long-run reversed-phase system was used. An Agilent 1290 instrument with a YMC Pro C4, 150×3.0 mm 3um column (YMC America, Allentown PA) stationary phase, a 5 μl injection loop volume, and the column and sample tray controlled at 23 °C was used to separate the analytes with the gradient shown in Table B. The analytes were detected at 210 nm, 230 nm, and 325 nm, and the peak identities were verified using LCMS. The analytes were separated into discrete peaks as specified in the table below.

[0322] Table A: List of analytes using the C4 reversed-phase method. The sum of all added intermediates gives the total amount of retinoid. "RT" means retention time.

[0323] Compound RT (min) λ max (nm) Dihydroactinidiolide 12.99 210 Farnesol 17.90 210 Z - Retinol 20.21 325 E - Retinol 20.32 325 Dihydroretinol 20.75 290 Z - Retinal 20.89 380 E - Retinal 21.02 380 Trans - retinol acetate 22.15 325 Cis - retinol acetate 22.35 325 Dihydroretinol acetate 22.6 290 Retinol palmitate 27.8 325 β - Carotene 28.9 325 Retinol oleate 29.3 325

[0324] Table B: Solvent Gradient Method

[0325] Solvent A:

[0326] Solvent B: Acetonitrile

[0327] Solvent C: Water

[0328] Solvent D: 1000 / 25 / 1 water / acetonitrile / methanesulfonic acid

[0329]

[0330] Method calibration. The method is calibrated using high-purity retinyl acetate received from DSM Nutritional Products, Kaiseraugst, CH. Retinol and retinaldehyde are quantified based on retinyl acetate. The dilutions described in Table 3 are prepared as follows. Weigh 40 mg of retinyl acetate into a 100 mL volumetric flask and dissolve it in ethanol to obtain a 400 μg / mL solution. Sonicate this solution as needed to ensure dissolution. Using 50 / 50 methanol / methyl tert-butyl ether (MTBE) as the diluent, dilute 5 mL of the 400 μg / mL solution to 50 mL (1 / 10 dilution, final concentration 40 μg / mL), dilute 5 mL to 100 mL (1 / 20 dilution, final concentration 20 μg / mL), dilute 5 mL of the 40 μg / mL to 50 mL (1 / 10 dilution, final concentration 4 μg / mL), and dilute 5 mL of the 20 μg / mL to 50 mL (1 / 10 dilution, 2 μg / mL). All dilutions are performed in volumetric flasks. The purity of retinyl acetate is determined by further diluting the 400 μg / mL stock solution 100-fold in ethanol (using a 2 mL volumetric pipette and a 200 mL volumetric flask). Use ethanol as the blank for the absorbance of this solution at 325 nm and adjust the initial concentration using the equation (absorbance * dilution factor (100) * molecular weight (328.5) / 51180 = concentration (mg / mL)). Since the ultraviolet (UV) absorbance of retinyl acetate maximizes rapidly, the lower the concentration, the better.

[0331] Table C.

[0332]

[0333]

[0334] Sample preparation. Precisely weigh 7 mg of the crystal and dissolve it in 10 mL of tetrahydrofuran (THF) before injection.

[0335] IsoparM quantification: The analysis of Isopar M is performed using the GC-FID method (see below).

[0336] To determine Isopar M, we use an Agilent 7890 instrument or a similar instrument with an HP-5 Agilent column that has a length of 30 m, an inner diameter of 0.25 mm, and a film thickness of 0.25 µm. H2 is used as the carrier gas with a flow rate of 1.7 mL / min. A 1-µL volume of the sample is injected at an inlet temperature of 250 °C with a split ratio of 50:1 to the FID detector. The detector temperature is set to 325 °C, the H2 flow rate is 40 mL / min, and the air flow rate is 250 mL / min. The oven temperature program is depicted in Table D.

[0337] Table D. GC Oven Temperature Program

[0338]

[0339] Method calibration

[0340] n-Decane is used as the internal standard (IS). The internal standard solution is prepared by diluting 500 µL of n-decane in a 50-mL volumetric flask with isopropanol (IPA, HPLC grade). The Isopar M standard solution is prepared by diluting 25 µL of accurately weighed Isopar M (Exxon Mobile) in 1 mL of the internal standard solution.

[0341] Isopar M is quantified based on the single-point response factor with respect to n-decane according to the following equation:

[0342]

[0343] Area IS = Area of the n-decane peak in the calibration run

[0344] Area I sopar M = Area of Isopar M in the calibration run

[0345] Weight IS = Weight of n-decane in the calibration run

[0346] Weight IsoparM = Weight of Isopar M in the calibration run

[0347] The retention times of Isopar M, the internal standard, and IPA are listed in Table E.

[0348] Table E. GC-FID Retention Times of Isopar M and n-Decane

[0349] The amount of Isopar M is calculated using the following equation:

[0350]

[0351] Wherein:

[0352] Area I sopar M = Area of Isopar M in sample analysis

[0353] Area IS = Area of internal standard peak in sample analysis

[0354] Weight ISTD = Weight of internal standard in sample preparation (mg)

[0355] Weight IsoparM = Sample weight (mg)

[0356] The result is presented as the percentage (%) of Isopar M in the product.

[0357] Sample preparation. 30 mg of accurately weighed crystals are dissolved in 10 mL of internal standard solution for injection.

[0358] The values measured by the above method are reported in Table 1 below. Below the row marked "Total" in Table 1 below, there are three additional calculated values. "Cis-isomer %" represents the ratio of the total amount of cis-isomers (in this case, the row marked "Cis-retinyl acetate") to the total weight of the retinoid component (in this case, expected to be the row marked "Retinyl acetate (all types)") (the "Cis-isomer %" is equal to the value in the row marked "Cis-retinyl acetate" divided by the value in the row marked "Retinyl acetate (all types)", expressed as % (i.e., multiplied by 100) and rounded to the nearest percentage point). "FARE" is determined by adding the amounts of retinyl palmitate and retinyl oleate detected in the composition (no other fatty acid retinyl esters are detected). Finally, "WSFRV" represents the weighted selected fermentation residue value, which is determined by adding the value obtained for the "Cis-isomer %" content to 10% of the determined "FARE" content.

[0359] Table 1 - Chemical Characterization

[0360] Unless otherwise stated, all amounts are in weight % relative to the entire composition.

[0361]

[0362] Oxidation Stability Thermal Stress Test

[0363] To determine the oxidative stability of Examples 1 to 5, each sample (prepared as described above) was placed in its own small brown glass vial under ambient conditions (preferably 20 °C and 50% relative humidity), blanketed with argon, and placed in an oven preheated to 105 °C. Then, the sample was held in the oven for 3 hours. After three hours, the sample was removed from the oven and analyzed via the same method used to determine the "initial" values reported in Table 1 above. The value of each component was measured after the thermal stress test and compared with the value determined before the test. Then, the relative difference between the second measurement and the first measurement was calculated, and the values are reported in Table 2 below. For clarity, Example 1 indicates that the total retinoid component before the thermal stress test (see the row labeled "All Retinyl Acetates (All Types)" in Table 1 above) was 90.53%; the -1.31% change indicated in Table 2 below means that the total retinoid component determined after the thermal stress test was 89.22% (by weight relative to the weight of the entire sample).

[0364] Table 2 - Thermal Stability Performance Specified as % Change Unless Otherwise Noted

[0365]

[0366] Bio-based Content

[0367] To determine the bio-based content, the sample was sent to Isolab GmbH Laboratorium für Stabil-Isotopenanalytik in Schweitenkirchen, Germany. The sample's 14 14C isotope content was analyzed using liquid scintillation counting. This laboratory also uses the QMA-M-03 method to determine the stable isotope ratios of 13 14C, 15 15N, 34 34S (using EA-IRMS), 18 18O (using equilibration-IRMS), and 2 2H (using HTC-IRMS) in plant-based food products and their ingredients. Then, the 14 14C content was calculated to determine the relative amount of carbon atoms in the sample that are from recently natural materials (i.e., excluding carbon atoms from fossil-based sources such as petroleum). The results are reported as "14C activity" in %. The results of this bio-based test for Example 6 are depicted in Table 3 below:

[0368] Table 3 - Bio-based Content

[0369] Specified as % Unless Otherwise Noted

[0370] Sample <![CDATA 14 C activity]]> Example 6 102.2％±3.7％

[0371] Antimicrobial efficacy test

[0372] The antimicrobial efficacy of retinol and retinyl acetate with different cis / trans ratios has been evaluated using a regulatory challenge test method (NF EN ISO 11930). Thus, under sterile conditions, solutions of the corresponding retinol and retinyl acetate mixtures (reference sample and the inventive mixture with a purity of about 98%) were prepared in physiological serum with 0.85 wt% NaCl. The presence of cis and trans isomers in the retinoid fraction was calculated by reverse-phase C4 HPLC analysis, where the total cis isomer content in the retinoid fraction is reported in Table 4 below along the row marked "cis / trans ratio" relative to the total weight of the trans isomers detected in the retinoid fraction. The specific retinoid used as the retinoid fraction is also reported for each sample (all samples are retinyl acetate or retinol).

[0373] The active substance solutions were then placed in 96-well deep plates (1.6 ml / well) at the concentrations specified in weight % in Table 4 below. The wells were contaminated separately with Propionibacterium acnes, Corynebacterium xerosis, and Malassezia furfur to obtain an initial contamination. The initial contamination count (which is shown in Table 4 below, listed as "initial inoculum count" for each test) was determined to be 100,000. After contamination, each well was mixed thoroughly to ensure uniform distribution of the microorganisms. Then each plate was incubated at 22 °C for 24 h. The (remaining) population was counted 24 hours after contamination, as indicated by the row marked "24 h" in Table 4 below. The change in count from the initial inoculum count to the 24-hour count (expressed as a percentage) is reflected in Table 4 below by the row marked "ΔR". The results are shown in Table 4 below.

[0374] Table 4 - Antimicrobial efficacy

[0375]

[0376]

[0377] Results discussion

[0378] According to Table 2, the results show that when compared with chemically synthesized analogs, various fermentatively produced retinoid-containing compositions (i.e., Examples 1 to 4) all have comparable or more excellent oxidative stability of the retinoid component (retinyl acetate in each of these examples), as indicated by the relative loss of retinyl acetate over the entire duration of the thermal stability test. Specifically, while the control (Example 5) exhibited a 5.50% reduction in retinyl acetate, Examples 2 to 4 performed similarly or slightly better, showing a reduction between 4.10 - 5.00%. Example 1 performed best, losing only 1.31% of its retinyl acetate content after undergoing the thermal stability test. This result is particularly surprising and unexpected given that the compositions of Examples 1 to 4 each contain one or more fermentation residue components, which are expected to have an adverse effect on the oxidative stability of such compositions.

[0379] As can be seen in Table 3, the carbon-14 activity of the substance composition indicated by Example 6 shows that - within the error range of the test - no proportion of fossil carbon could be detected. Thus, according to this test, such samples can be considered to be completely "bio-based". This result can be similarly applied to each of Examples 1 to 4, which were prepared via a similar method and using the same carbon source during the fermentation process.

[0380] As can be seen in Table 4, specific cis / trans mixtures of retinyl acetate and retinol according to the present invention have excellent effects in anti-acne applications, namely inhibiting the growth of Propionibacterium acnes. Retinyl acetate mixtures with cis-isomer contents of 0.49% (Example 8) and 0.25% (Example 9) were able to reduce Propionibacterium acnes by approximately 30%, while a reference with a cis-isomer content of 3% allowed 270% growth of the bacteria. Similar effects were also observed in the retinol-containing compositions, where a retinol composition with a cis-isomer content of 0.3% (Example 11) reduced the bacteria by 99.3%, compared to a similar composition with a cis-isomer content of 1% that only reduced the bacteria by 99.0%. Commercially available trans-retinol and trans-retinyl acetate (e.g., dry vitamin A acetate 500 or retinol 50C from BASF or A) respectively have efficacy against the growth of Propionibacterium acnes within the same range as the reference sample (not shown).

[0381] A similar trend regarding the activity against Corynebacterium xerosis and Malassezia furfur can be observed from Table 4. Notably, when tested against Corynebacterium xerosis, as observed in each of Examples 7, 8, and 9, an increase in the concentration of the retinoid-containing composition has the effect of further enhancing the antimicrobial efficacy.

[0382] Finally, certain compositions having retinol as the retinoid component were shown to have enhanced potency against the dandruff-causing bacterium Malassezia furfur. Specifically, the results showed that a composition with a cis-isomer content of 0.1% reduced the activity by 60%, while a composition with a cis-isomer content of 1% neither reduced the activity of the same bacterium nor allowed the growth of the same bacterium.

[0383] Additional exemplary embodiments

[0384] See the claims.

[0385] Unless otherwise specified, the term weight % refers to the amount by mass of a particular component relative to the entire liquid radiation-curable composition into which it is incorporated.

[0386] Unless otherwise indicated herein or clearly contradicted by the context, the use of the terms "a", "an", "the", and similar indicatives in the context of describing the present invention (especially in the context of the following claims) shall be construed to cover both the singular and the plural. Unless otherwise stated, the terms "comprising", "having", "including", and "containing" shall be construed as open-ended terms (i.e., meaning "including but not limited to"). Unless otherwise indicated herein, the description of a range of values herein is merely intended to serve as a shorthand method of referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise claimed, the use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to better illustrate the invention and does not limit the scope of the invention. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0387] This document describes the preferred embodiments of the present invention, including the best mode known to the inventors for carrying out the present invention. After reading the foregoing description, variations of those preferred embodiments will be apparent to those of ordinary skill in the art. The inventors expect those skilled in the art to appropriately employ such variations, and the inventors expect the present invention to be practiced in a manner different from that specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. In addition, unless otherwise stated herein or clearly contradicted by context, the present invention encompasses any combination of all possible variations of the above-described elements.

[0388] Although the present invention has been described in detail with reference to specific embodiments thereof, it will be apparent to those of ordinary skill in the art that various changes and modifications can be made thereto without departing from the spirit and scope of the claimed invention.

[0389] Table 5 - Sequence Listing

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

Claims

1. A substance composition for use in food, feed, pharmaceuticals, or cosmetic care products, said substance composition comprising, consisting of, or consisting essentially of the following substances: (i) A retinoid component comprising a mixture of cis and trans isomers; and (ii) Its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; wherein the cis isomer is present in an amount less than 3% by weight relative to the weight of the entire retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%.

2. The composition according to claim 1, wherein the fermentation residue comprises fatty acid retinyl ester (FARE), retinal, retinol, farnesol, a fermentation carbon source, or β-carotene.

3. The composition according to any one of the preceding claims, wherein the composition has a weighted selected fermentation residue value (WSFRV) between 0.1 and 2.5, or between 0.1 and 2.0, or between 0.1 and 1.0, or between 0.1 and 0.9, or between 0.4 and 2.5, or between 0.4 and 2.0, or between 0.4 and 1.0, or between 0.4 and 0.9, or between 0.6 and 2.5, or between 0.6 and 2.0, or between 0.6 and 1.0, or between 0.5 and 0.9, wherein the WSFRV is determined according to the following formula: WSFRV = C + 0.1×F where C = the weight percentage of the cis isomer present relative to the total amount of the retinoid component (i) and the fermentation residue (ii), and F = the weight percentage of the FARE present relative to the total amount of the retinoid component (i) and the fermentation residue (ii).

4. The composition according to claim 1 or 2, wherein the retinoid component comprises, consists of, or consists essentially of a compound according to formula (I): R is -CHO, -CH2OH, -COOH, -CH(R 1 )2, -CH2OR 2 , -COOR 3 , -CONHR 4 , or -CO(NR 4 )2, R 1 is independently a lower alkoxy group, or R 1 ' and R 1 " together are a lower alkylenedioxy group, R 2 is an alkanoyl or an aroyl group, R 3 is an alkyl group, an aryl group or an aralkyl group; and R 4 、R 4' and R 4" are independently hydrogen, alkyl, aryl or aralkyl; wherein the term "lower alkoxy" is an alkoxy group having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, or propoxy; the term "lower alkylenedioxy" is a group that also contains 1 to 6 carbon atoms, such as methylenedioxy or ethylenedioxy, and wherein the alkyl or alkylenedi part may be straight-chain or branched, depending on the number of carbon atoms; the term "alkanoyl" refers to a straight-chain or branched alkanoyl having 1 to 18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl, and palmitoyl; the term "aroyl" refers to aromatic carboxylic acids having 7 and 11 carbon atoms, including benzoyl or naphthoyl, respectively; the term "alkyl" is a straight-chain or branched alkyl group having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl, or octadecyl; The term "aryl", either by itself or as part of "aralkyl", is phenyl or naphthyl; and The term "aralkyl" encompasses groups having 1 to 4 carbon atoms in the aliphatic moiety, such as benzyl and phenylpropyl.

5. The composition according to any one of the preceding claims, wherein the retinoid component comprises retinol or a retinyl ester, consists of retinol or a retinyl ester, or consists essentially of retinol or a retinyl ester, and wherein the retinyl ester comprises retinyl acetate or retinyl palmitate, consists of retinyl acetate or retinyl palmitate, or consists essentially of retinyl acetate or retinyl palmitate.

6. The composition according to any one of the preceding claims, wherein the retinoid component comprises retinyl acetate, consists of retinyl acetate, or consists essentially of retinyl acetate.

7. The composition according to any one of the preceding claims, wherein the retinoid component comprises a mixture of cis and trans isomers, and wherein the cis isomers are present in the following amounts by weight relative to the weight of the entire mixture between 0.1 - 3% by weight, or between 0.2 - 3% by weight, or between 0.4 - 3% by weight, or between 0.5 - 3% by weight; or between 0.1 - 2.5% by weight, or between 0.2 - 2.5% by weight, or between 0.4 - 2.5% by weight, or between 0.5 - 2.5% by weight; or between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.4 - 2% by weight, or between 0.5 - 2% by weight; or between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.4 - 1.5% by weight, or between 0.5 - 1.5% by weight; or between 0.1 - 1% by weight, or between 0.2 - 1% by weight, or between 0.4 - 1% by weight, or between 0.5 - 1% by weight; or between 0.1 - 0.9% by weight, or between 0.2 - 0.9% by weight, or between 0.4 - 0.9% by weight, or between 0.5 - 0.9% by weight.

8. The composition according to any one of the preceding claims, wherein if the retinoid component is retinol, the cis isomers include 9 - cis retinol, 11 - cis retinol, 13 - cis retinol, 9,13 - di - cis retinol, 11,13 - di - cis retinol, 13 - cis - 3,4 - dehydroretinol, 9 - cis - 3,4 - dehydroretinol, and / or 9,13 - di - cis - 3,4 - dehydroretinol; or if the retinoid component is retinal, the cis isomers include 13 - cis retinal, 11 - cis retinal, 11,13 - di - cis retinal, 9,13 - di - cis retinal, 9 - cis retinal, 13 - cis - 3,4 - dehydroretinal, and / or 11,13 - di - cis - 3,4 - dehydroretinal; or If the retinoid component is retinol acetate, the cis isomers include one or more of all corresponding cis forms of retinol acetate.

9. The composition according to any one of the preceding claims, wherein the fermentation residue comprises FARE, β-carotene, retinol, retinal, and a fermented carbon source.

10. The composition according to any one of the preceding claims, wherein the fermentation residue comprises retinol, and wherein the retinol comprises all-E retinol, consists of all-E retinol, or consists essentially of all-E retinol.

11. The composition according to any one of the preceding claims, wherein the fermentation residue comprises retinal, and wherein the retinal comprises 9Z-retinal, consists of 9Z-retinal, or consists essentially of 9Z-retinal.

12. The composition according to any one of the preceding claims, wherein the fermentation residue comprises one or more FARE, and wherein the one or more FARE are present in an amount of less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt% relative to the total weight of the retinoid component present.

13. The composition according to any one of the preceding claims, wherein the composition comprises FARE in an amount between 0.05 - 4 wt%, or between 0.1 - 4 wt%, or between 0.15 - 4 wt%, or between 0.2 - 4 wt% relative to the total weight of the retinoid component present, or between 0.05 - 3 wt%, or between 0.1 - 3 wt%, or between 0.15 - 3 wt%, or between 0.2 - 3 wt% of FARE; or between 0.05 - 2 wt%, or between 0.1 - 2 wt%, or between 0.15 - 2 wt%, or between 0.2 - 2 wt% of FARE; or between 0.05 - 1 wt%, or between 0.1 - 1 wt%, or between 0.15 - 1 wt%, or between 0.2 - 1 wt% of FARE.

14. The composition according to any one of the preceding claims, wherein the FARE comprises retinol palmitate and / or retinol oleate.

15. The composition according to any one of the preceding claims, wherein the fermentation residue comprises 9Z-retinal, and wherein the 9Z-retinal is present in an amount of less than 10 wt%, or less than 8 wt%, or less than 6 wt%, or less than 5 wt%, or less than 3 wt% relative to the total weight of the retinal component present.

16. The composition according to any one of the preceding claims, wherein the composition comprises 9Z-retinal in an amount of from 0.1 to 10% by weight, or from 0.5% to 10% by weight, or from 1% to 10% by weight, or from 1.5% to 10% by weight, based on the total weight of the retinoid component present; Or between 0.1 - 8 wt%, or between 0.5 wt% to 8 wt%, or between 1 wt% to 8 wt%, or between 1.5 wt% to 8 wt% of 9Z-retinal; Or between 0.1 - 6 wt%, or between 0.5 wt% to 6 wt%, or between 1 wt% to 6 wt%, or between 1.5 wt% to 6 wt% of 9Z-retinal; Or 9Z-retinal between 0.1 - 5% by weight, or between 0.5% and 5% by weight, or between 1% and 5% by weight, or between 1.5% and 5% by weight; or 9Z-retinal between 0.1 - 3% by weight, or between 0.5% and 3% by weight, or between 1% and 3% by weight, or between 1.5% and 3% by weight.

17. The composition according to any one of the preceding claims, wherein the fermentation residue contains β-carotene, and wherein the β-carotene is present in an amount of less than 4% by weight, or less than 3% by weight, or less than 2% by weight, or less than 1% by weight, or less than 0.5% by weight, relative to the total weight of the retinoid component present.

18. The composition according to any one of the preceding claims, wherein the composition contains β-carotene between 0 - 4% by weight, or between 0.2 - 4% by weight, or between 0.5 - 4% by weight, or between 1 - 4% by weight, relative to the total weight of the retinoid component present, or between 0 - 3% by weight, or between 0.2 - 3% by weight, or between 0.5 - 3% by weight, or between 1 - 3% by weight, or between 0 - 2% by weight, or between 0.2 - 2% by weight, or between 0.5 - 2% by weight, or between 1 - 2% by weight, or between 0 - 1% by weight, or between 0.2 - 1% by weight, or between 0.5 - 1% by weight, or between 0 - 0.5% by weight, or between 0.2 - 0.5% by weight.

19. The composition according to any one of the preceding claims, wherein the fermentation residue contains farnesol, and wherein the farnesol is present in an amount of less than 10,000 parts per million (ppm), or less than 5,000 ppm, 1,000 ppm, or less than 100 ppm, or less than 10 ppm, or less than 5 ppm, or less than 2 ppm, relative to the total weight of the retinoid component present.

20. The composition according to any one of the preceding claims, wherein the composition contains farnesol between 0 - 10,000 ppm, or between 2 - 10,000 ppm, or between 5 - 10,000 ppm, or between 10 - 10,000 ppm, or between 100 - 10,000 ppm, relative to the total weight of the retinoid component present; or between 0 - 5,000 ppm, or between 2 - 5,000 ppm, or between 5 - 5,000 ppm, or between 10 - 5,000 ppm, or between 100 - 5,000 ppm; or Farnesol in the range of 0 - 1,000 ppm, or 2 - 1,000 ppm, or 5 - 1,000 ppm, or 10 - 1,000 ppm, or 100 - 1,000 ppm; or Farnesol in the range of 0 - 100 ppm, or 2 - 100 ppm, or 5 - 100 ppm, or 10 - 100 ppm.

21. The composition according to any one of the preceding claims, wherein the composition is free of farnesol.

22. The composition according to any one of the preceding claims, wherein the fermented carbon source comprises, consists of, or consists essentially of a biological carbon source.

23. The composition according to any one of the preceding claims, wherein the fermented carbon source comprises straight-chain alkanes, free fatty acids, ethanol, glucose, including triglycerides, especially vegetable oils, including the corresponding free fatty acids therefrom, such as oleic acid, palmitic acid, or linoleic acid.

24. The composition according to any one of the preceding claims, wherein the fermentation residue comprises ethanol or glucose, and wherein ethanol or glucose is present in an amount of less than 2 wt%, or less than 1 wt%, or less than 0.75 wt% relative to the total weight of the retinoid component present.

25. The composition according to any one of the preceding claims, wherein the composition comprises ethanol or glucose in an amount between 0.05% by weight and 2% by weight, or between 0.1% by weight and 2% by weight, or between 0.2% by weight and 2% by weight, relative to the total weight of the retinoid component present; Or ethanol or glucose in the range of 0.05 wt% to 1 wt%, or 0.1 wt% to 1 wt%, or 0.2 wt% to 1 wt%; Or ethanol or glucose in the range of 0.05 wt% to 0.5 wt%, or 0.1 wt% to 0.5 wt%, or 0.2 wt% to 0.5 wt%.

26. The composition according to any one of the preceding claims, wherein the fermentation residue comprises an isoparaffinic fluid.

27. The composition according to any one of the preceding claims, wherein the isoparaffinic fluid is present in an amount of less than 3 wt%, or less than 2 wt%, or less than 1.5 wt%, or less than 1.25 wt% relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

28. The composition according to any one of the preceding claims, wherein the isoparaffinic fluid is present in an amount of between 0.1 - 2 wt%, or between 0.2 - 2 wt%, or between 0.5 - 2 wt%, or between 0.1 - 1.5 wt%, or between 0.2 - 1.5 wt%, or between 0.5 - 1.5 wt% relative to the weight of the entire retinoid component (i) and its fermentation residue (ii); and / or the isoparaffinic fluid comprises Isopar M, consists of Isopar M, or consists essentially of Isopar M.

29. The composition according to any one of the preceding claims, wherein the fermentation residue comprises a dihydro form of the retinoid component.

30. The composition according to any one of the preceding claims, wherein the dihydro form is present in an amount of less than 0.5% by weight, or less than 0.25% by weight, or less than 0.1% by weight, or less than 0.05% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

31. The composition according to any one of the preceding claims, wherein the dihydro form is present in an amount between 0.01 - 0.5% by weight, or between 0.01 - 0.25% by weight, or between 0.01 - 0.1% by weight, or between 0.01 - 0.05% by weight, or between 0.03 - 0.5% by weight, or between 0.03 - 0.25% by weight, or between 0.03 - 0.1% by weight, or between 0.03 - 0.05% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

32. The composition according to the preceding claim, wherein the dihydro form of the retinoid component comprises, consists of, or consists essentially of dihydroretinyl acetate.

33. The composition according to any one of the preceding claims, wherein the fermentation residue contains less than 0.5% by weight, or less than 0.2% by weight, or less than 0.1% by weight of rosafluene, lycopene, ergosterol, and dihydro-β-ionone, or is substantially free of rosafluene, lycopene, ergosterol, and dihydro-β-ionone.

34. The composition according to any one of the preceding claims, wherein the cis isomer is present in an amount of less than 1% by weight based on the weight of the overall mixture of the cis isomer and the trans isomer. and / or Among them, FARE is present in an amount of less than 3.5% by weight, or less than 1.5% by weight, relative to the total weight of the retinoid component.

35. The composition according to any one of the preceding claims, wherein the retinoid component is present in a weight ratio of greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:1, relative to its fermentation residue.

36. The composition according to any one of the preceding claims, wherein the retinoid component is present relative to its fermentation residue in a weight ratio of between 4:1 to 100:1, or between 5:1 to 100:1, or between 6:1 to 100:1, or between 10:1 to 100:1, or between 20:1 to 100:1, or between 25:1 to 100:1; or between 4:1 to 50:1, or between 5:1 to 50:1, or between 6:1 to 50:1, or between 10:1 to 50:1, or between 20:1 to 50:1, or between 25:1 to 50:1; or a weight ratio between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or a weight ratio between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

37. The composition according to any one of the preceding claims, wherein the retinoid component comprises retinyl acetate, consists of retinyl acetate or consists essentially of retinyl acetate, and wherein the retinyl acetate is present in a weight ratio greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:1 relative to its fermentation residue.

38. The composition according to any one of the preceding claims, wherein the retinoid component comprises retinyl acetate, consists of retinyl acetate or consists essentially of retinyl acetate, and wherein the retinyl acetate is present relative to its fermentation residue in: a weight ratio between 4:1 and 100:1, or between 5:1 and 100:1, or between 6:1 and 100:1, or between 10:1 and 100:1, or between 20:1 and 100:1, or between 25:1 and 100:1; or a weight ratio between 4:1 and 50:1, or between 5:1 and 50:1, or between 6:1 and 50:1, or between 10:1 and 50:1, or between 20:1 and 50:1, or between 25:1 and 50:1; or a weight ratio between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or a weight ratio between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

39. The composition according to any one of the preceding claims, wherein the bio-based carbon content of the material composition is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

40. The composition according to any one of the preceding claims, wherein the bio-based carbon content of the retinoid component (i) and its fermentation residue (ii) is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

41. The composition according to any one of the preceding claims, wherein the bio-based carbon content is determined by ASTM D6866-20 or 14 C and 13 C isotope characterization.

42. The composition according to any one of the preceding claims, wherein the amount of retinyl acetate, measured relative to the weight of the entire composition, is within 5 wt%, or within 4 wt%, or within 3 wt% of the amount of retinyl acetate present in the composition after subjecting the composition to a thermal stability test by heating the composition to 105 degrees Celsius for 3 hours.

43. The composition according to any one of the preceding claims, wherein the composition is in crystalline form.

44. The composition according to any one of the preceding claims, wherein the crystalline form comprises a plurality of crystals, and the average particle length D of the plurality of crystals determined by a microscopy imaging method 50 is greater than 100 microns, or greater than 200 microns, or greater than 300 microns, or greater than 400 microns, or between 100 - 1200 microns, or between 100 - 1000 microns, or between 100 - 800 microns, or between 200 - 1200 microns, or between 200 - 1000 microns, or between 200 - 800 microns.

45. The composition according to any one of the preceding claims, wherein the composition further comprises a solvent.

46. The composition according to any one of the preceding claims, wherein the solvent comprises ethanol or glucose.

47. The composition according to any one of the preceding claims, wherein in the composition, the retinoid component (i) and its fermentation residue (ii) are present as an emulsion in oil.

48. The composition according to any one of the preceding claims, wherein the emulsion in oil comprises a fat-soluble antioxidant and an oil.

49. The composition according to any one of the preceding claims, wherein the oil preferably comprises triglycerides, such as vegetable oils and / or fats, and the fat-soluble antioxidant comprises ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, tert-butylhydroxyquinoline, ethoxyquin and / or ascorbyl esters of fatty acids.

50. A preparation comprising the composition according to any one of the preceding claims.

51. The preparation according to the preceding claim, wherein the preparation is an animal feed premix.

52. The preparation according to the preceding claim, wherein the animal feed premix comprises a matrix component and an additive preferably comprising silica.

53. The composition or preparation according to any one of claims 1 - 52; wherein the animal feed premix comprises at least one additional micronutrient.

54. The composition or preparation according to any one of claims 1 - 50, wherein the composition or preparation is a cosmetic composition.

55. The composition or preparation according to the preceding claim, wherein the cosmetic composition comprises (a) the composition according to any one of claims 1 - 49; and (b) a pharmaceutically or cosmetically acceptable carrier, water and at least one reagent selected from the group consisting of surfactants, emulsifiers, thickeners, oils and mixtures thereof.

56. The cosmetic composition according to the preceding claim, wherein the composition is a shampoo product, a hair conditioner, an oil-in-water emulsion, a water-in-oil emulsion or a gel.

57. The composition according to any one of claims 1 - 49, wherein the composition is a food or beverage for human consumption.

58. The composition according to any one of claims 1 - 49, wherein the preparation is a pharmaceutical composition or a dietary supplement.

59. A method for fermenting to produce a retinoid-containing composition, the method comprising the following steps: (a) Cultivate a microorganism under conditions allowing the production of a fermentation product; (b) Isolate the fermentation product to produce an isolated retinoid-containing composition; wherein the isolated retinoid-containing composition comprises (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue, wherein the cis isomer is present in an amount less than 3% by weight based on the weight of the whole retinoid component.

60. The method according to any one of the preceding claims, wherein the isolation step further comprises one or more steps of distilling, crystallizing, filtering and / or washing the produced fermentation product.

61. The method according to any one of the preceding claims, the method further comprising drying the isolated retinoid-containing composition to produce a dry retinoid crystal composition.

62. The method according to any one of the preceding claims, the method further comprising saponifying the isolated retinoid-containing composition and / or the dry retinoid crystal composition to produce a retinol product.

63. The method according to the preceding claim, the method further comprising isolating the retinol product to produce an isolated retinol composition.

64. The method according to the preceding claim, wherein the step of isolating the retinol product further comprises one or more steps of distilling, crystallizing, filtering and / or washing the isolated retinol product.

65. The method according to the preceding claim, wherein the isolated retinoid-containing composition, the dry retinoid crystal composition and / or the isolated retinol composition comprises, consists of or consists essentially of the composition according to any one of claims 1-49.

66. The method for fermentatively producing a retinoid-containing composition according to any one of the preceding claims, wherein the isolated retinoid-containing composition, the dry retinoid crystal composition or the isolated retinol composition comprises (i) a retinoid component comprising a mixture of cis and trans isomers, and (ii) its fermentation residue; Among them, the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; and wherein the cis isomer is present in an amount less than 3% by weight based on the weight of the whole retinoid component.

67. The method for fermentatively producing a retinoid-containing composition according to the preceding claim, wherein the fermentation residue comprises fatty acid retinyl ester (FARE), retinal, retinol, farnesol, a fermentation carbon source or β-carotene.

68. A method for fermenting to produce a retinol-containing composition according to any one of the preceding claims, wherein the composition has a weighted selection fermentation residue value (WSFRV) between 0.1 and 2.5, or between 0.1 and 2.0, or between 0.1 and 1.0, or between 0.1 and 0.9, or between 0.4 and 2.5, or between 0.4 and 2.0, or between 0.4 and 1.0, or between 0.4 and 0.9, or between 0.6 and 2.5, or between 0.6 and 2.0, or between 0.6 and 1.0, or between 0.5 and 0.9, wherein the WSFRV is determined according to the following formula: WSFRV = C + 0.1×F wherein C = the weight percentage of the cis isomer present relative to the total amount of the retinol component (i) and the fermentation residue (ii), and F = the weight percentage of the FARE present relative to the total amount of the retinol component (i) and the fermentation residue (ii).

69. A method according to any one of the preceding method claims, wherein the retinol component comprises, consists of, or consists essentially of a compound according to formula (I): R is -CHO, -CH2OH, -COOH, -CH(R 1 )2, -CH2OR 2 , -COOR 3 , -CONHR 4 , or -CO(NR 4 )2, R 1 is independently a lower alkoxy group, or R 1 ' and R 1 " together form a lower alkylenedioxy group, R 2 is an alkanoyl or an aroyl group, R 3 is an alkyl, aryl or aralkyl group; and R 4 、R 4' and R 4" are independently hydrogen, alkyl, aryl or aralkyl; wherein the term "lower alkoxy" is an alkoxy group having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, or propoxy; the term "lower alkylenedioxy" is a group that also contains 1 to 6 carbon atoms, such as methylenedioxy or ethylenedioxy, and wherein the alkyl or alkylidene moiety can be straight-chain or branched, depending on the number of carbon atoms; the term "alkanoyl" refers to a straight-chain or branched alkanoyl group having 1 to 18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl, and palmitoyl; the term "aroyl" refers to aromatic carboxylic acids having 7 and 11 carbon atoms, including benzoyl or naphthoyl, respectively; the term "alkyl" is a straight-chain or branched alkyl group having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl, or octadecyl; the term "aryl" by itself or as part of "aralkyl" is phenyl or naphthyl; and the term "aralkyl" encompasses groups that have 1 to 4 carbon atoms in the aliphatic part, such as benzyl and phenylpropyl.

70. A method according to any one of the preceding method claims, wherein the retinol component comprises, consists of, or consists essentially of retinol or a retinyl ester, wherein the retinyl ester comprises, consists of, or consists essentially of retinyl acetate or retinyl palmitate.

71. A method according to any one of the preceding method claims, wherein the retinol component comprises, consists of, or consists essentially of retinyl acetate.

72. The method according to any one of the preceding method claims, wherein the retinoid component comprises a mixture of cis and trans isomers, and wherein the cis isomer is present in the following weight ratios relative to the weight of the entire mixture between 0.1 - 3% by weight, or between 0.2 - 3% by weight, or between 0.4 - 3% by weight, or between 0.5 - 3% by weight; or between 0.1 - 2.5% by weight, or between 0.2 - 2.5% by weight, or between 0.4 - 2.5% by weight, or between 0.5 - 2.5% by weight; or between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.4 - 2% by weight, or between 0.5 - 2% by weight; or between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.4 - 1.5% by weight, or between 0.5 - 1.5% by weight; or between 0.1 - 1% by weight, or between 0.2 - 1% by weight, or between 0.4 - 1% by weight, or between 0.5 - 1% by weight; or between 0.1 - 0.9% by weight, or between 0.2 - 0.9% by weight, or between 0.4 - 0.9% by weight, or between 0.5 - 0.9% by weight.

73. The method according to any one of the preceding method claims, wherein if the retinoid component is retinol, the cis isomers include 9 - cis retinol, 11 - cis retinol, 13 - cis retinol, 9,13 - di - cis retinol, 11,13 - di - cis retinol, 13 - cis - 3,4 - dehydroretinol, 9 - cis - 3,4 - dehydroretinol, and / or 9,13 - di - cis - 3,4 - dehydroretinol; or if the retinoid component is retinal, the cis isomers include 13 - cis retinal, 11 - cis retinal, 11,13 - di - cis retinal, 9,13 - di - cis retinal, 9 - cis retinal, 13 - cis - 3,4 - dehydroretinal, and / or 11,13 - di - cis - 3,4 - dehydroretinal; or if the retinoid component is retinol acetate, the cis isomers include one or more of all corresponding cis forms of retinol acetate.

74. The method according to any one of the preceding method claims, wherein the fermentation residue comprises FARE, β - carotene, retinol, retinal, and a fermentation carbon source.

75. The method according to any one of the preceding method claims, wherein the fermentation residue comprises retinol, and wherein the retinol comprises all - trans retinol, consists of all - trans retinol, or consists essentially of all - trans retinol.

76. The method according to any one of the preceding method claims, wherein the fermentation residue comprises retinal, and wherein the retinal comprises 9Z - retinal, consists of 9Z - retinal, or consists essentially of 9Z - retinal.

77. The method according to any one of the preceding method claims, wherein the fermentation residue comprises one or more FAREs, and wherein the one or more FAREs are present in an amount of less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt% relative to the total weight of the retinoid component present.

78. The method according to any one of the preceding method claims, wherein the composition comprises FAREs in an amount between 0.05 - 4 wt%, or between 0.1 - 4 wt%, or between 0.15 - 4 wt%, or between 0.2 - 4 wt% relative to the total weight of the retinoid component present, or between 0.05 - 3 wt%, or between 0.1 - 3 wt%, or between 0.15 - 3 wt%, or between 0.2 - 3 wt% of FAREs; or between 0.05 - 2 wt%, or between 0.1 - 2 wt%, or between 0.15 - 2 wt%, or between 0.2 - 2 wt% of FAREs; or between 0.05 - 1 wt%, or between 0.1 - 1 wt%, or between 0.15 - 1 wt%, or between 0.2 - 1 wt% of FAREs.

79. The method according to any one of the preceding claims, wherein the FARE comprises retinol palmitate and / or retinol oleate.

80. The method according to any one of the preceding method claims, wherein the fermentation residue comprises 9Z - retinal, and wherein the 9Z - retinal is present in an amount of less than 10 wt%, or less than 8 wt%, or less than 6 wt%, or less than 5 wt%, or less than 3 wt% relative to the total weight of the retinal component present.

81. A method according to any one of the preceding method claims, wherein the composition comprises 9Z-retinal in an amount between 0.1 and 10% by weight, or between 0.5% and 10% by weight, or between 1% and 10% by weight, or between 1.5% and 10% by weight, based on the total weight of the retinoid component present; Or 9Z - retinal in an amount between 0.1 - 8 wt%, or between 0.5 wt% to 8 wt%, or between 1 wt% to 8 wt%, or between 1.5 wt% to 8 wt%; Or 9Z - retinal in an amount between 0.1 - 6 wt%, or between 0.5 wt% to 6 wt%, or between 1 wt% to 6 wt%, or between 1.5 wt% to 6 wt%; Or 9Z - retinal in an amount between 0.1 - 5 wt%, or between 0.5 wt% to 5 wt%, or between 1 wt% to 5 wt%, or between 1.5 wt% to 5 wt%; Or 9Z - retinal in an amount between 0.1 - 3 wt%, or between 0.5 wt% to 3 wt%, or between 1 wt% to 3 wt%, or between 1.5 wt% to 3 wt%.

82. The method according to any one of the preceding method claims, wherein the fermentation residue comprises β - carotene, and wherein the β - carotene is present in an amount of less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt%, or less than 0.5 wt% relative to the total weight of the retinoid component present.

83. A method according to any one of the preceding method claims, wherein the composition comprises β-carotene in an amount between 0 and 4% by weight, or between 0.2 and 4% by weight, or between 0.5 and 4% by weight, or between 1 and 4% by weight, relative to the total weight of the retinoid component present, or β-carotene in an amount between 0 and 3% by weight, or between 0.2 and 3% by weight, or between 0.5 and 3% by weight, or between 1 and 3% by weight, or β-carotene in an amount between 0 and 2% by weight, or between 0.2 and 2% by weight, or between 0.5 and 2% by weight, or between 1 and 2% by weight, or β-carotene in an amount between 0 and 1% by weight, or between 0.2 and 1% by weight, or between 0.5 and 1% by weight, or β-carotene in an amount between 0 and 0.5% by weight, or between 0.2 and 0.5% by weight.

84. A method according to any one of the preceding method claims, wherein the fermentation residue comprises farnesol, and wherein the farnesol is present in an amount less than 10,000 parts per million (ppm), or less than 5,000 ppm, 1,000 ppm, or less than 100 ppm, or less than 10 ppm, or less than 5 ppm, or less than 2 ppm, relative to the total weight of the retinoid component present.

85. A method according to any one of the preceding method claims, wherein the composition comprises farnesol in an amount between 0 and 10,000 ppm, or between 2 and 10,000 ppm, or between 5 and 10,000 ppm, or between 10 and 10,000 ppm, or between 100 and 10,000 ppm, relative to the total weight of the retinoid component present; or farnesol in an amount between 0 and 5,000 ppm, or between 2 and 5,000 ppm, or between 5 and 5,000 ppm, or between 10 and 5,000 ppm, or between 100 and 5,000 ppm; or farnesol in an amount between 0 and 1,000 ppm, or between 2 and 1,000 ppm, or between 5 and 1,000 ppm, or between 10 and 1,000 ppm, or between 100 and 1,000 ppm; or farnesol in an amount between 0 and 100 ppm, or between 2 and 100 ppm, or between 5 and 100 ppm, or between 10 and 100 ppm.

86. A method according to any one of the preceding method claims, wherein the composition is free of farnesol.

87. A method according to any one of the preceding method claims, wherein the fermentable carbon source comprises, consists of, or consists essentially of a biological carbon source.

88. The method according to any one of the preceding method claims, wherein the fermented carbon source comprises linear alkanes, free fatty acids, ethanol, glucose, including triglycerides, in particular vegetable oils, including the corresponding free fatty acids derived therefrom, such as oleic acid, palmitic acid or linoleic acid.

89. The method according to any one of the preceding method claims, wherein the fermentation residue comprises ethanol or glucose, and wherein the ethanol or glucose is present in an amount of less than 2% by weight, or less than 1% by weight, or less than 0.75% by weight, relative to the total weight of the retinoid component present.

90. A method according to any one of the preceding method claims, wherein the composition comprises ethanol or glucose in an amount between 0.05% and 2% by weight, or between 0.1% and 2% by weight, or between 0.2% and 2% by weight, relative to the total weight of the retinoid component present; Or ethanol or glucose between 0.05% and 1% by weight, or between 0.1% and 1% by weight, or between 0.2% and 1% by weight; Or ethanol or glucose between 0.05% and 0.5% by weight, or between 0.1% and 0.5% by weight, or between 0.2% and 0.5% by weight.

91. The method according to any one of the preceding method claims, wherein the fermentation residue comprises an isoparaffinic fluid.

92. The method according to any one of the preceding method claims, wherein the isoparaffinic fluid is present in an amount of less than 3% by weight, or less than 2% by weight, or less than 1.5% by weight, or less than 1.25% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

93. The method according to any one of the preceding method claims, wherein the isoparaffinic fluid is present in an amount between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.5 - 2% by weight, or between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.5 - 1.5% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii); and / or the isoparaffinic fluid comprises Isopar M, consists of Isopar M or consists essentially of Isopar M.

94. The method according to any one of the preceding method claims, wherein the fermentation residue comprises a dihydro form of the retinoid component.

95. The method according to any one of the preceding method claims, wherein the dihydro form is present in an amount of less than 0.5% by weight, or less than 0.25% by weight, or less than 0.1% by weight, or less than 0.05% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

96. The method according to any one of the preceding method claims, wherein the dihydro form is present in an amount, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii), of between 0.01 - 0.5 wt%, or between 0.01 - 0.25 wt%, or between 0.01 - 0.1 wt%, or between 0.01 - 0.05 wt%, or between 0.03 - 0.5 wt%, or between 0.03 - 0.25 wt%, or between 0.03 - 0.1 wt%, or between 0.03 - 0.05 wt%.

97. The method according to the preceding claim, wherein the dihydro form of the retinoid component comprises, consists of, or consists essentially of dihydroretinyl acetate.

98. The method according to any one of the preceding method claims, wherein the fermentation residue contains less than 0.5 wt%, or less than 0.2 wt%, or less than 0.1 wt% of rosafluene, lycopene, ergosterol, and dihydro-β-ionone, or is substantially free of rosafluene, lycopene, ergosterol, and dihydro-β-ionone.

99. The method according to any one of the preceding method claims, wherein the cis isomer is present in an amount by weight of less than 1 wt% relative to the total weight of the cis and trans isomer mixture. and / or Among them, FARE is present in an amount of less than 3.5 wt% or less than 1.5 wt% relative to the total weight of the retinoid component.

100. The method according to any one of the preceding method claims, wherein the retinoid component is present in a weight ratio relative to its fermentation residue of greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:

1.

101. The method according to any one of the preceding method claims, wherein the retinoid component is present relative to its fermentation residue in the following: a weight ratio between 4:1 to 100:1, or between 5:1 to 100:1, or between 6:1 to 100:1, or between 10:1 to 100:1, or between 20:1 to 100:1, or between 25:1 to 100:1; or a weight ratio between 4:1 to 50:1, or between 5:1 to 50:1, or between 6:1 to 50:1, or between 10:1 to 50:1, or between 20:1 to 50:1, or between 25:1 to 50:1; or a weight ratio between 4:1 to 35:1, or between 5:1 to 35:1, or between 6:1 to 35:1, or between 10:1 to 35:1, or between 20:1 to 35:1, or between 25:1 to 35:1; or A weight ratio between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

102. The method according to any one of the preceding method claims, wherein the retinoid component comprises, consists of, or consists essentially of retinyl acetate, and wherein the retinyl acetate is present in a weight ratio greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:1 relative to its fermentation residue.

103. The method according to any one of the preceding method claims, wherein the retinoid component comprises, consists of, or consists essentially of retinyl acetate, and wherein the retinyl acetate is present relative to its fermentation residue in a weight ratio between: 4:1 and 100:1, or between 5:1 and 100:1, or between 6:1 and 100:1, or between 10:1 and 100:1, or between 20:1 and 100:1, or between 25:1 and 100:1; or between 4:1 and 50:1, or between 5:1 and 50:1, or between 6:1 and 50:1, or between 10:1 and 50:1, or between 20:1 and 50:1, or between 25:1 and 50:1; or between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

104. The method according to any one of the preceding method claims, wherein the bio-based carbon content of the substance composition is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

105. The method according to any one of the preceding method claims, wherein the bio-based carbon content of the retinoid component (i) and its fermentation residue (ii) is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

106. The method according to any one of the preceding method claims, wherein the bio-based carbon content is determined by ASTM D6866-20 or 14 C and 13 C isotope characterization.

107. The method according to any one of the preceding method claims, wherein the amount of retinyl acetate measured relative to the weight of the entire composition is within 5 wt%, or within 4 wt%, or within 3 wt% of the amount of retinyl acetate present in the composition after subjecting the composition to a thermal stability test by heating the composition to 105 degrees Celsius for 3 hours.

108. The method according to any one of the preceding method claims, wherein the composition is in crystalline form.

109. The method according to any one of the preceding method claims, wherein the crystalline form comprises a plurality of crystals, and the average particle length D of the plurality of crystals determined by a microscopy imaging method 50 is greater than 100 microns, or greater than 200 microns, or greater than 300 microns, or greater than 400 microns, or between 100 and 1200 microns, or between 100 and 1000 microns, or between 100 and 800 microns, or between 200 and 1200 microns, or between 200 and 1000 microns, or between 200 and 800 microns.

110. The method according to any one of the preceding claims, wherein the composition further comprises a solvent.

111. The method according to any one of the preceding claims, wherein the solvent comprises ethanol or glucose.

112. The method according to any one of the preceding claims, wherein in the composition, the retinoid component (i) and its fermentation residue (ii) are present as an emulsion in oil.

113. The method according to any one of the preceding claims, wherein the emulsion in oil comprises a fat-soluble antioxidant and an oil.

114. The method according to any one of the preceding claims, wherein the oil preferably comprises triglycerides, such as vegetable oils and / or fats, and the fat-soluble antioxidant comprises ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, tert-butylhydroxyquinoline, ethoxyquin, and / or ascorbyl esters of fatty acids.

115. The method according to any one of the preceding claims, wherein the method further comprises the step of combining the isolated retinoid-containing composition, the dry retinoid crystal composition, and / or the isolated retinol product with one or more other food, feed, pharmaceutical, or personal care additive components.

116. A method for preparing a food, feed, pharmaceutical, or personal care (pre)product, the method comprising the steps of: (a) providing a substance composition comprising, consisting of, or consisting essentially of: (i) a retinoid component comprising a mixture of cis and trans isomers; and (ii) its fermentation residue; wherein the retinoid component is present in a weight ratio greater than 4:1 relative to its fermentation residue; optionally wherein the cis isomer is present in an amount less than 3% by weight, by weight, relative to the total weight of the retinoid component; optionally further wherein the bio-based carbon content of (i) and (ii) is greater than 50%, or greater than 60%, or greater than 70%, or greater than 90%; and (b) formulating the substance composition to produce a formulation, preferably for use as a food, feed, pharmaceutical, or personal care (pre)product.

117. The method for preparing a food, feed, pharmaceutical, or personal care (pre)product according to the preceding claim, wherein the fermentation residue comprises fatty acid retinyl esters (FARE), retinal, retinol, farnesol, a fermentable carbon source, or β-carotene.

118. A method for preparing a food, feed, pharmaceutical or personal care (pre) - product according to any one of the preceding claims, wherein the composition has a weighted selected fermentation residue value (WSFRV) between 0.1 and 2.5, or between 0.1 and 2.0, or between 0.1 and 1.0, or between 0.1 and 0.9, or between 0.4 and 2.5, or between 0.4 and 2.0, or between 0.4 and 1.0, or between 0.4 and 0.9, or between 0.6 and 2.5, or between 0.6 and 2.0, or between 0.6 and 1.0, or between 0.5 and 0.9, wherein the WSFRV is determined according to the following formula: WSFRV = C + 0.1×F wherein C = the weight percentage of the cis - isomer present relative to the total amount of the retinoid component (i) and the fermentation residue (ii), and F = the weight percentage of the FARE present relative to the total amount of the retinoid component (i) and the fermentation residue (ii).

119. A method for preparing a food, feed, pharmaceutical or personal care (pre) - product according to any one of the preceding claims, wherein the retinoid component comprises, consists of, or consists essentially of a compound according to formula (I): R is -CHO, -CH2OH, -COOH, -CH(R 1 )2, -CH2OR 2 , -COOR 3 , -CONHR 4 , or -CO(NR 4 )2, R 1 is independently a lower alkoxy group, or R 1 ' and R 1 " together form a lower alkylenedioxy group, R 2 is an alkanoyl or an aroyl group, R 3 is an alkyl, aryl or aralkyl group; and R 4 、R 4' and R 4" are independently hydrogen, alkyl, aryl or aralkyl; wherein the term "lower alkoxy" is an alkoxy group having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy or propoxy; the term "lower alkylenedioxy" is a group which also contains 1 to 6 carbon atoms, such as methylenedioxy or ethylenedioxy, and wherein the alkyl or alkylenyl moiety may be straight - chain or branched, depending on the number of carbon atoms; the term "alkanoyl" refers to a straight - chain or branched alkanoyl having 1 to 18 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, stearoyl and palmitoyl; the term "aroyl" refers to aromatic carboxylic acids having 7 and 11 carbon atoms, including benzoyl or naphthoyl, respectively; the term "alkyl" is a straight - chain or branched alkyl group having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, butyl, decyl, dodecyl, hexadecyl or octadecyl; the term "aryl" by itself or as part of an "aralkyl" is phenyl or naphthyl; and the term "aralkyl" encompasses groups which have 1 to 4 carbon atoms in the aliphatic part, such as benzyl and phenylpropyl.

120. A method for preparing a food, feed, pharmaceutical or personal care (pre) - product according to any one of the preceding claims, wherein the retinoid component comprises retinol or retinyl ester, consists of retinol or retinyl ester, or consists essentially of retinol or retinyl ester, wherein the retinyl ester comprises retinyl acetate or retinyl palmitate, consists of retinyl acetate or retinyl palmitate, or consists essentially of retinyl acetate or retinyl palmitate.

121. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the retinoid component comprises, consists of or consists essentially of retinyl acetate.

122. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the retinoid component comprises a mixture of cis and trans isomers, and the cis isomers are present in the following amounts by weight relative to the weight of the entire mixture between 0.1 - 3% by weight, or between 0.2 - 3% by weight, or between 0.4 - 3% by weight, or between 0.5 - 3% by weight; or between 0.1 - 2.5% by weight, or between 0.2 - 2.5% by weight, or between 0.4 - 2.5% by weight, or between 0.5 - 2.5% by weight; or between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.4 - 2% by weight, or between 0.5 - 2% by weight; or between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.4 - 1.5% by weight, or between 0.5 - 1.5% by weight; or between 0.1 - 1% by weight, or between 0.2 - 1% by weight, or between 0.4 - 1% by weight, or between 0.5 - 1% by weight; or between 0.1 - 0.9% by weight, or between 0.2 - 0.9% by weight, or between 0.4 - 0.9% by weight, or between 0.5 - 0.9% by weight.

123. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein if the retinoid component is retinol, the cis isomers include 9-cis retinol, 11-cis retinol, 13-cis retinol, 9,13-dicis retinol, 11,13-dicis retinol, 13-cis-3,4-dehydroretinol, 9-cis-3,4-dehydroretinol and / or 9,13-dicis-3,4-dehydroretinol; or if the retinoid component is retinal, the cis isomers include 13-cis retinal, 11-cis retinal, 11,13-dicis retinal, 9,13-dicis retinal, 9-cis retinal, 13-cis-3,4-dehydroretinal and / or 11,13-dicis-3,4-dehydroretinal; or if the retinoid component is retinyl acetate, the cis isomers include one or more of all corresponding cis forms of retinyl acetate.

124. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fermentation residue comprises FARE, β-carotene, retinol, retinal and a fermentation carbon source.

125. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fermentation residue comprises retinol, and wherein the retinol comprises E-retinol, consists of E-retinol or consists essentially of E-retinol.

126. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fermentation residue comprises retinal, and wherein the retinal comprises 9Z-retinal, consists of 9Z-retinal or consists essentially of 9Z-retinal.

127. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fermentation residue comprises one or more FAREs, and wherein the one or more FAREs are present in an amount of less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt%, relative to the total weight of the retinoid components present.

128. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the composition comprises FARE in an amount between 0.05 - 4 wt%, or between 0.1 - 4 wt%, or between 0.15 - 4 wt%, or between 0.2 - 4 wt%, relative to the total weight of the retinoid components present, or between 0.05 - 3 wt%, or between 0.1 - 3 wt%, or between 0.15 - 3 wt%, or between 0.2 - 3 wt%; or between 0.05 - 2 wt%, or between 0.1 - 2 wt%, or between 0.15 - 2 wt%, or between 0.2 - 2 wt%; or between 0.05 - 1 wt%, or between 0.1 - 1 wt%, or between 0.15 - 1 wt%, or between 0.2 - 1 wt%.

129. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the FARE comprises retinol palmitate and / or retinol oleate.

130. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fermentation residue comprises 9Z-retinal, and wherein the 9Z-retinal is present in an amount of less than 10 wt%, or less than 8 wt%, or less than 6 wt%, or less than 5 wt%, or less than 3 wt%, relative to the total weight of the retinal components present.

131. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the composition comprises between 0.1 and 10% by weight, or between 0.5 and 10% by weight, or between 1 and 10% by weight, or between 1.5 and 10% by weight of 9Z-retinal, relative to the total weight of the retinoid component present; Or between 0.1 - 8 wt%, or between 0.5 wt% to 8 wt%, or between 1 wt% to 8 wt%, or between 1.5 wt% to 8 wt% of 9Z-retinal; Or 9Z-retinal in an amount between 0.1 - 6% by weight, or between 0.5% and 6% by weight, or between 1% and 6% by weight, or between 1.5% and 6% by weight; or 9Z-retinal in an amount between 0.1 - 5% by weight, or between 0.5% and 5% by weight, or between 1% and 5% by weight, or between 1.5% and 5% by weight; or 9Z-retinal in an amount between 0.1 - 3% by weight, or between 0.5% and 3% by weight, or between 1% and 3% by weight, or between 1.5% and 3% by weight.

132. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue comprises β-carotene, and wherein the β-carotene is present in an amount of less than 4% by weight, or less than 3% by weight, or less than 2% by weight, or less than 1% by weight, or less than 0.5% by weight, relative to the total weight of the retinoid components present.

133. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the composition comprises β-carotene in an amount between 0 - 4% by weight, or between 0.2 - 4% by weight, or between 0.5 - 4% by weight, or between 1 - 4% by weight, relative to the total weight of the retinoid components present, or β-carotene in an amount between 0 - 3% by weight, or between 0.2 - 3% by weight, or between 0.5 - 3% by weight, or between 1 - 3% by weight, or β-carotene in an amount between 0 - 2% by weight, or between 0.2 - 2% by weight, or between 0.5 - 2% by weight, or between 1 - 2% by weight, or β-carotene in an amount between 0 - 1% by weight, or between 0.2 - 1% by weight, or between 0.5 - 1% by weight, or β-carotene in an amount between 0 - 0.5% by weight, or between 0.2 - 0.5% by weight.

134. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue comprises farnesol, and wherein the farnesol is present in an amount of less than 10,000 parts per million (ppm), or less than 5,000 ppm, 1,000 ppm, or less than 100 ppm, or less than 10 ppm, or less than 5 ppm, or less than 2 ppm, relative to the total weight of the retinoid components present.

135. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the composition comprises farnesol in an amount of between 0 - 10,000 ppm, or between 2 - 10,000 ppm, or between 5 - 10,000 ppm, or between 10 - 10,000 ppm, or between 100 - 10,000 ppm, based on the total weight of the retinoid component present; or farnesol in an amount of between 0 - 5,000 ppm, or between 2 - 5,000 ppm, or between 5 - 5,000 ppm, or between 10 - 5,000 ppm, or between 100 - 5,000 ppm; or farnesol in an amount of between 0 - 1,000 ppm, or between 2 - 1,000 ppm, or between 5 - 1,000 ppm, or between 10 - 1,000 ppm, or between 100 - 1,000 ppm; or farnesol in an amount of between 0 - 100 ppm, or between 2 - 100 ppm, or between 5 - 100 ppm, or between 10 - 100 ppm.

136. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the composition is free of farnesol.

137. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentable carbon source comprises, consists of or consists essentially of a biological carbon source.

138. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentable carbon source comprises straight-chain alkanes, free fatty acids, ethanol, glucose, including triglycerides, in particular vegetable oils, including the corresponding free fatty acids therefrom, such as oleic acid, palmitic acid or linoleic acid.

139. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue comprises ethanol or glucose, and wherein ethanol or glucose is present in an amount of less than 2 wt%, or less than 1 wt%, or less than 0.75 wt%, based on the total weight of the retinoid component present.

140. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the composition comprises ethanol or glucose in an amount between 0.05% by weight and 2% by weight, or between 0.1% by weight and 2% by weight, or between 0.2% by weight and 2% by weight, relative to the total weight of the retinoid component present; Or ethanol or glucose in an amount of between 0.05 wt% and 1 wt%, or between 0.1 wt% and 1 wt%, or between 0.2 wt% and 1 wt%; Or ethanol or glucose in an amount of between 0.05 wt% and 0.5 wt%, or between 0.1 wt% and 0.5 wt%, or between 0.2 wt% and 0.5 wt%.

141. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue comprises an isoparaffinic fluid.

142. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the isoparaffinic fluid is present in an amount of less than 3% by weight, or less than 2% by weight, or less than 1.5% by weight, or less than 1.25% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

143. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the isoparaffinic fluid is present in an amount between 0.1 - 2% by weight, or between 0.2 - 2% by weight, or between 0.5 - 2% by weight, or between 0.1 - 1.5% by weight, or between 0.2 - 1.5% by weight, or between 0.5 - 1.5% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii); and / or the isoparaffinic fluid comprises Isopar M, consists of Isopar M, or consists essentially of Isopar M.

144. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue comprises the dihydro form of the retinoid component.

145. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the dihydro form is present in an amount of less than 0.5% by weight, or less than 0.25% by weight, or less than 0.1% by weight, or less than 0.05% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

146. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the dihydro form is present in an amount between 0.01 - 0.5% by weight, or between 0.01 - 0.25% by weight, or between 0.01 - 0.1% by weight, or between 0.01 - 0.05% by weight, or between 0.03 - 0.5% by weight, or between 0.03 - 0.25% by weight, or between 0.03 - 0.1% by weight, or between 0.03 - 0.05% by weight, relative to the weight of the entire retinoid component (i) and its fermentation residue (ii).

147. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to the preceding claim, wherein the dihydro form of the retinoid component comprises, consists of, or consists essentially of dihydroretinyl acetate.

148. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fermentation residue contains less than 0.5% by weight, or less than 0.2% by weight, or less than 0.1% by weight of rosafluene, phytoene, ergosterol and dihydro-β-ionone, or is substantially free of rosafluene, phytoene, ergosterol and dihydro-β-ionone.

149. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the cis isomer is present in an amount of less than 1% by weight based on the weight of the overall mixture of the cis isomer and the trans isomer. and / or Among them, FARE is present in an amount of less than 3.5% by weight, or less than 1.5% by weight, relative to the total weight of the retinoid component.

150. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the retinoid component is present in a weight ratio of greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:1 relative to its fermentation residue.

151. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the retinoid component is present relative to its fermentation residue in the following: a weight ratio between 4:1 and 100:1, or between 5:1 and 100:1, or between 6:1 and 100:1, or between 10:1 and 100:1, or between 20:1 and 100:1, or between 25:1 and 100:1; or a weight ratio between 4:1 and 50:1, or between 5:1 and 50:1, or between 6:1 and 50:1, or between 10:1 and 50:1, or between 20:1 and 50:1, or between 25:1 and 50:1; or a weight ratio between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or a weight ratio between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

152. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the retinoid component comprises, consists of or consists essentially of retinyl acetate, and wherein the retinyl acetate is present in a weight ratio of greater than 5:1, or greater than 6:1, or greater than 10:1, or greater than 20:1, or greater than 25:1 relative to its fermentation residue.

153. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the retinoid component comprises, consists of or consists essentially of retinyl acetate, and wherein the retinyl acetate is present relative to its fermentation residue in a weight ratio of between 4:1 and 100:1, or between 5:1 and 100:1, or between 6:1 and 100:1, or between 10:1 and 100:1, or between 20:1 and 100:1, or between 25:1 and 100:1; or between 4:1 and 50:1, or between 5:1 and 50:1, or between 6:1 and 50:1, or between 10:1 and 50:1, or between 20:1 and 50:1, or between 25:1 and 50:1; or between 4:1 and 35:1, or between 5:1 and 35:1, or between 6:1 and 35:1, or between 10:1 and 35:1, or between 20:1 and 35:1, or between 25:1 and 35:1; or between 4:1 and 30:1, or between 5:1 and 30:1, or between 6:1 and 30:1, or between 10:1 and 30:1, or between 20:1 and 30:1, or between 25:1 and 30:

1.

154. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the bio-based carbon content of the substance composition is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

155. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the bio-based carbon content of the retinoid component (i) and its fermentation residue (ii) is greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

156. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the bio-based carbon content is determined by ASTM D6866-20 or 14 C and 13 C isotope characterization.

157. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the amount of retinyl acetate, measured relative to the weight of the entire composition, is within 5% by weight, or within 4% by weight, or within 3% by weight of the amount of retinyl acetate present in the composition after subjecting the composition to a thermal stability test by heating the composition to 105 °C for 3 hours.

158. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the composition is present in crystalline form.

159. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the crystalline form comprises a plurality of crystals, and the average particle length D of the plurality of crystals determined by a microscopy imaging method 50 is greater than 100 microns, or greater than 200 microns, or greater than 300 microns, or greater than 400 microns, or between 100 - 1200 microns, or between 100 - 1000 microns, or between 100 - 800 microns, or between 200 - 1200 microns, or between 200 - 1000 microns, or between 200 - 800 microns.

160. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the composition further comprises a solvent.

161. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the solvent comprises ethanol.

162. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein in the composition, the retinoid component (i) and its fermentation residue (ii) are present as an emulsion in oil.

163. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the emulsion in oil comprises a fat-soluble antioxidant and an oil.

164. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the oil preferably comprises triglycerides, such as vegetable oils and / or fats, and the fat-soluble antioxidant comprises ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, tert-butylhydroxyquinoline, ethoxyquin and / or ascorbyl esters of fatty acids.

165. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the formulation step (b) comprises the following sub-steps: (1) Dissolving the matrix component in water to produce a matrix solution; (2) Heating the substance composition according to any one of the preceding claims, optionally preferably also heating the substance composition according to any one of the preceding claims in oil, to produce an active phase; (3) Emulsifying the active phase into the matrix solution to obtain a dispersion; and (4) Drying the dispersion in the presence of a capture medium to obtain at least one microgranule.

166. A method for preparing a food, feed, pharmaceutical or personal care (pre)-product according to any one of the preceding claims, wherein the formulation step (b) further comprises the sub-step of (5) heating the dispersion and / or spray-drying the dispersion.

167. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the matrix component comprises one or more hydrocolloids, consists of one or more hydrocolloids or consists essentially of one or more hydrocolloids.

168. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the one or more hydrocolloids include gelatin, xanthan gum, gum acacia, pectin, guar gum, carob gum, alginate, cellulose or a cellulose derivative, or a combination thereof.

169. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the cellulose derivative includes carboxymethyl cellulose and / or a modified polysaccharide.

170. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the modified polysaccharide includes a modified food starch.

171. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the matrix component includes a modified (food) starch, pectin, alginate, carrageenan, furcellaran, chitosan, maltodextrin, a dextrin derivative, cellulose and a cellulose derivative (such as cellulose acetate, methyl cellulose, hydroxypropyl methyl cellulose), lignosulfonate, a polysaccharide gum (such as gum acacia, gum arabic, linseed gum, indian gum, tamarind gum and arabinogalactan), gelatin (bovine gelatin, fish gelatin, porcine gelatin, poultry gelatin), a plant protein (such as pea, soybean, castor bean, cotton, potato, sweet potato, cassava, rapeseed, sunflower, sesame, linseed, safflower, lentil, nut, wheat, rice, corn, barley, rye, oat, lupin and sorghum), an animal protein (including milk protein or whey protein), lecithin, a polyglycerol fatty acid ester, a monoglycerol fatty acid ester, a diglycerol fatty acid ester, a sorbitan ester, a PG ester and a sugar ester (and their derivatives).

172. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein a fat-soluble antioxidant is added in the formulation step (b).

173. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fat-soluble antioxidant includes ascorbic acid or a salt thereof, tocopherol, butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), propyl gallate, tert-butyl hydroxyquinoline, ethoxyquin and / or an ascorbyl ester of a fatty acid.

174. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the fat-soluble antioxidant is added to the substance composition and the oil in the heating sub-step (2).

175. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the oil comprises, consists of or consists essentially of triglycerides.

176. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the triglycerides comprise vegetable oils and / or fats.

177. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the vegetable oils and / or fats comprise corn oil, sunflower oil, (hydrogenated) soybean oil, safflower oil, rapeseed oil, peanut oil, (hydrogenated) palm oil, palm kernel oil, cottonseed oil and / or coconut oil, including their fractionation characteristics.

178. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the capture medium comprises corn starch or an organic or inorganic anti-caking agent.

179. A microgranule produced by the method according to any one of claims 165 - 178.

180. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the stabilization preparation comprises, consists of or consists essentially of the microgranules according to claim 179 and / or is produced by the method according to any one of claims 165 - 178.

181. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the formulation step (b) comprises the following sub-steps: (1) Introducing the substance composition, matrix component, water and oil according to any one of the preceding claims into an extruder having an orifice; (2) Extruding the substance composition, the matrix component, the water and the oil through the orifice to produce an extrudate.

182. The method according to the preceding claim, wherein the extrudate comprises an emulsion of the substance composition and the oil in the water and the matrix component, wherein the emulsion is formed inside the extruder.

183. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the substance composition and the oil are introduced into the extruder together as a pre-mixed active phase.

184. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the formulation step (b) further comprises the following sub-steps: (3) Cutting the extrudate into discrete particles; and (4) Optionally, drying the discrete particles.

185. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the formulation step (b) further comprises the step of directing a cooling fluid stream onto the orifice and the extrudate.

186. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the cooling fluid is configured to flow along a cooling flow axis and the extrudate is configured to be extruded through an outlet axis, and wherein the cooling flow axis and the outlet axis are substantially anti-parallel and / or substantially collinear.

187. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the matrix component comprises one or more hydrocolloids, consists of one or more hydrocolloids or consists essentially of one or more hydrocolloids.

188. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the one or more hydrocolloids include gelatin, xanthan gum, acacia gum, pectin, guar gum, carob gum, alginate, cellulose or cellulose derivatives, or combinations thereof.

189. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the cellulose derivatives include carboxymethyl cellulose and / or modified polysaccharides.

190. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the modified polysaccharides include modified food starch.

191. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the matrix component includes modified (food) starch, pectin, alginate, carrageenan, furcellaran, chitosan, maltodextrin, dextrin derivatives, cellulose and cellulose derivatives (such as cellulose acetate, methyl cellulose, hydroxypropyl methyl cellulose), lignosulfonate, polysaccharide gums (such as acacia gum, gum arabic, linseed gum, indian gum, tamarind gum and arabinogalactan), gelatin (bovine gelatin, fish gelatin, porcine gelatin, poultry gelatin), vegetable proteins (such as peas, soybeans, castor seeds, cotton, potatoes, sweet potatoes, cassava, rapeseed, sunflower, sesame, linseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, oats, lupins and sorghum), animal proteins (including milk proteins or whey proteins), lecithin, polyglycerol fatty acid esters, monoglycerol fatty acid esters, diglycerol fatty acid esters, sorbitan esters, PG esters and sugar esters (and their derivatives).

192. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein a fat-soluble antioxidant is added to the extruder.

193. A method for preparing a food, feed, pharmaceutical or personal care (pre-) product according to any one of the preceding claims, wherein the fat-soluble antioxidant includes ascorbic acid or its salts, tocopherols, butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), propyl gallate, tert-butyl hydroxyquinoline, ethoxyquin and / or ascorbyl esters of fatty acids.

194. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the oil comprises, consists of or consists essentially of triglycerides.

195. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the triglycerides comprise vegetable oils and / or fats.

196. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the vegetable oils and / or fats comprise corn oil, sunflower oil, (hydrogenated) soybean oil, safflower oil, rapeseed oil, peanut oil, (hydrogenated) palm oil, palm kernel oil, cottonseed oil and / or coconut oil, including their fractionation characteristics.

197. An extrudate produced by a method according to any one of claims 181 - 196.

198. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the stabilization preparation comprises, consists of or consists essentially of the extrudate according to claim 197 and / or is produced by a method according to any one of claims 181 - 196.

199. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, the method further comprising step (c) of combining the stabilization preparation with one or more additives to produce a food, feed, pharmaceutical or personal care product.

200. A method for preparing a food, feed, pharmaceutical or personal care (pre) product according to any one of the preceding claims, wherein the personal care product comprises a lotion, a wash, a thickened emulsion, a gel, a cream, a milk, an ointment, a paste, a powder, a cosmetic, a solid stick, an aerosol, a mousse, a foam and / or a spray.

201. Use of the microcapsules according to claim 179 and / or the extrudate according to claim 197 in foods, feeds, pharmaceuticals, personal care products.

202. A food, feed, pharmaceutical or personal care product comprising the microcapsules according to claim 179 and / or the extrudate according to claim 197.

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