Poly(amino acid) based capsules

Abstract

To provide a poly(amino acid) capsule and a synthesis method for preparing the poly(amino acid) capsule.SOLUTION: There is provided a capsule consisting of a polymeric shell surrounding a core. The core comprises an organic compound, the polymeric shell comprises a poly(amino acid) and is obtainable by interfacial polymerization of a N-carboxy-anhydride monomer according to a general structure (I). The organic compound is a marine oil, a vegetable oil, an essential oil, a fragrance, a flavour, an insect repellent, a flame retardant, an active pharmaceutical ingredient or an agrochemical. In the general structure (I): an n represents 0 or 1; and R1, R2 and R3 represent hydrogen, substituted or unsubstituted alkyl groups, etc., and atoms necessary to form a five- to eight-membered ring.SELECTED DRAWING: None

Description

[Technical Field]

[0001] It is an object of the present invention to provide poly(amino acid)-based capsules. It is a further object of the present invention to provide synthetic methods for preparing poly(amino acid)-based capsules. [Background technology]

[0002] Biodegradability of polymers is an ever-increasing demand in all applications, especially those where there is a risk that the polymer will eventually reach the environment. Therefore, more and more bio-based approaches are emerging in various technical fields. Encapsulation is a very promising technology for the controlled release of various chemicals, such as bioactive products or fragrances, to protect hydrolysis-sensitive compounds in aqueous formulations and to separate reactants in single-fluid formulations. In particular, life sciences, agrochemicals, and cosmetics are major application fields of encapsulation, where the release of encapsulated chemicals into the environment or contact with biological environments is unavoidable. Therefore, biodegradability and biocompatibility are absolute requirements in all of these applications.

[0003] Nanocapsules and microcapsules can be prepared using both chemical and physical methods. Encapsulation methods include complex coacervation, liposome formation, spray drying, and precipitation and polymerization. For engineering applications, interfacial polymerization is a particularly suitable technique. This technique has been reviewed by [1] and [2].

[0004] Polymerization methods are particularly preferred because they allow the most control in capsule design. More preferably, interfacial polymerization, most preferably interfacial polycondensation, is used to prepare capsules for industrial use. In interfacial polymerization, polymerization occurs at the interface of oil droplets in an oil-in-water emulsion or at the interface of water droplets in a water-in-oil emulsion. In interfacial polycondensation, two reactants meet at the interface of emulsion droplets and react rapidly.

[0005] Generally, interfacial polymerization requires a lipophilic phase dispersed in an aqueous continuous phase, or vice versa. Classically, each phase contains at least one dissolved monomer (first shell component), which can react with another monomer (second shell component) dissolved in the other phase. Upon polymerization, a polymer is formed that is insoluble in both the aqueous and lipophilic phases. As a result, the formed polymer tends to precipitate at the interface between the lipophilic and aqueous phases, thereby forming a shell around the dispersed phase, which grows upon further polymerization.

[0006] Interfacial polymerization techniques known in the prior art often rely on the polymerization of petroleum-based synthetic monomers, resulting in shell chemistries typically selected from polyamides, polyureas, polyurethanes, polyesters, polycarbonates, or combinations thereof. Polycondensates of aldehydes with other monomers, such as melamine or urea, are also well documented in the literature. However, generally, all of the shell chemistries result in polymers with little or no decomposition.

[0007] Poly(amino acids) are a well-known class of biocompatible and biodegradable polymers and appear to be a suitable class of shell polymers for biocompatible microcapsule and nanocapsule design. However, classical interfacial polycondensation, as described above, is not a suitable method for preparing poly(amino acid)-based capsules.

[0008] Poly(amino acids) are synthesized by the synthesis of N-carboxyanhydride monomers (NCAs) in heterogeneous aqueous solvent systems. (2003) described the preparation of glycopeptide microparticles using acylated chitosan as a starting material as an initiator for graft polymerization of NCA in a heterogeneous aqueous solvent system. The disclosed microparticles were prepared using L-leucine as the amino acid. The particles were tens of microns to hundreds of microns in size and did not contain any specific core material.

[0009] Jacobs et al. (2004) reported miniemulsion polymerization using NCA in a heterogeneous aqueous solvent system. The particle size was in the 200 nm range. However, the particles did not contain core material. Particle deformation due to secondary structuring of the particles was observed.

[0010] In many approaches, amphiphilic block copolymers containing poly(amino acid) blocks are prepared separately and then assembled into micelle-like capsules or transferred into capsules using a coacervation-type approach. Self-assembly of the amphiphilic block copolymer into micelles can hold up the core material. A drawback of micelle-based capsules is that they have a shell that is much weaker than that of capsules with a polymer shell. Therefore, cross-linking of the micelle shell is required in many systems.

[0011] Patent Document 1 discloses the production of microparticles via cavity formation in amphiphilic polyamino acid block copolymers. Stable microparticles can only be achieved for a specific hydrophobic-hydrophilic balance of the block copolymer, and therefore the number of suitable amino acid polymers is significantly limited.

[0012] In the literature, e.g., Non-Patent Document 5, different block copolymer-based micelles have been reported as an encapsulation technique. However, this approach requires a first step of separate synthesis of the amphiphilic block copolymer, which must be fully controlled and tailored to the compound or functional group that needs to be encapsulated. In a second step, micelles are formed in a liquid medium. This process must be repeated for each different functional group to be encapsulated. By its very nature, the micellar approach is vulnerable to different process conditions (e.g., pH of the aqueous medium, ionic strength), limiting the flexibility of industrialization.

[0013] Micelle-like capsules often require a liquid medium to maintain their spherical structure, e.g., to retain the core material inside the micelle. Therefore, isolating micelles in a dry state is very difficult or impossible. In contrast to capsules obtained by interfacial polymerization, micelle-like capsules are limited in the range of particle sizes they can obtain, more specifically, in a smaller particle size range. Furthermore, although amphiphilic block copolymer approaches allow for good control of the polymer structure, the preparation of well-defined polymers requires extensive synthetic procedures, which makes these approaches less suitable for technological applications than interfacial polymerization-based techniques.

[0014] Other encapsulation techniques, such as complex coacervation, require tightly controlled operating process windows, which are often very narrow, limiting the flexibility of the technique on an industrial scale.

[0015] Therefore, there remains a need for an encapsulation approach to design poly(amino acid)-based capsules with a wide variety of particle sizes, with mechanically strong shells, that can be isolated in a dry state, and that can be obtained in a one-step process. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] WO96 / 40279 [Non-patent literature]

[0017] [Non-Patent Document 1] Zhang Y. and Rochefort D., Journal of Microencapsulation, 29(7), 636-649 (2012) [Non-patent document 2] Salauen F., Encapsulation Nanotechnologies, Vikas Mittal (ed.), chapter 5, 137-173 (Scrivener Publishing LLC (2013)) [Non-patent document 3] Wang et al., Journal of Biomedical Research Part B: Applied Biomaterials, 89B(1), 45-54 (2009) [Non-patent document 4] Jacobs et al., J. Am. Soc., 141, 12522-12526 (2019) [Non-patent document 5] ianxun Ding, Nanotechnology 22 (2011) 494012 Summary of the Invention

[0018] It has now been found that poly(amino acid)-based core-shell structures obtained by interfacial ring-opening polymerization of monomers according to general structure I are capable of realizing the objects of the present invention.

[0019] The present invention comprises a capsule, as defined in claim 1, consisting of a poly(amino acid)-based polymeric shell surrounding a core.

[0020] According to another aspect, the present invention comprises a method for preparing a capsule according to claim 1. This method is defined in claim 11.

[0021] Other features, elements, steps, characteristics and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention. Specific embodiments of the invention are also defined in the dependent claims. DETAILED DESCRIPTION OF THE INVENTION

[0022] A. Capsule The object of the present invention is realized by a core-shell structure, wherein the core comprises an organic compound and the shell comprises an oligo- or poly(amino acid), which is obtained by oligomerization or polymerization of at least one N-carboxy-anhydride monomer according to the general structure 1. [ka] During the ceremony n represents 0 or 1. R1, R2, and R3 are each independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkene group, or a substituted or unsubstituted alkyl group. a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl or heteroaryl group; Any of R1, R2, and R3 can represent the atoms necessary to form a five- to eight-membered ring.

[0023] Preferably, the organic compound is a compound of substantially low volatility, defined as having a boiling point of at least 150°C at 1013 mPas.

[0024] More preferably, the organic compound is a hydrophobic compound, which has an octanol-water partition coefficient of log K ow Without being bound by any theory, it is believed that the hydrophobic compounds in the lipophilic droplets keep the poly(amino acid) chains with hydrophilic character that are formed on the outside of the droplets during interfacial polymerization, resulting in a strong and dense spherical polymer shell.

[0025] The particle size of the capsules of the present invention is preferably 0.05 μm to 10 μm, more preferably 0.07 μm to 5 μm, and most preferably 0.1 μm to 3 μm. Capsules of the present invention having a particle size of less than 1 μm are particularly preferred.

[0026] A.1. N-Carboxy-anhydride Monomers In preferred embodiments, n represents 0. In particularly preferred embodiments, R3 represents hydrogen or an alkyl group, with hydrogen being most preferred.

[0027] In another preferred embodiment, R1 and R2 are selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, and a substituted or unsubstituted aryl group.

[0028] In a further preferred embodiment, the N-carboxy-anhydride monomer according to the general structure is selected from the group consisting of glycine derivatives, alanine derivatives, leucine derivatives, phenylalanine derivatives, phenylglycine derivatives, valine derivatives, glutamic acid derivatives, aspartic acid derivatives, lysine derivatives, ornithine derivatives, histidine derivatives, methionine derivatives, cysteine ​​derivatives, arginine derivatives, tryptophan derivatives, cysteine ​​derivatives, isoleucine derivatives, tyrosine derivatives, proline derivatives, and serine derivatives. Both D- and L-amino acid derivatives and mixtures thereof can be used.

[0029] Exemplary N-carboxy-anhydride monomers are provided in Table 1, but are not limited thereto. [Table 1-1] [Table 1-2]

[0030] N-Carboxy-anhydrides (NCAs) have been prepared using a variety of synthetic methods, the earliest of which is known as the Leuchs method, which starts with the chloroformate acylation of an amino acid followed by conversion to the corresponding NCA via its acid chloride. Several variations of this method have been published by Wessely and Katschalski, using the mixed anhydride method and conversion with PBr3, respectively. Perhaps the best-known method is the Fuchs-Farting method, which uses phosgene for the direct conversion of amino acids to the corresponding NCA. For safety reasons, phosgene has been replaced by diphosgene or triphosgene in subsequent studies. Over the last few years, Several phosgene-free methods have been described, including a review by Secker et al. (Macromol. Biosci., 15, 881-891 (2015)).

[0031] A.2. Encapsulation Method The capsules according to the present invention are prepared using a ring-opening polymerization method, more preferably interfacial ring-opening polymerization.

[0032] The interfacial polymerization method according to the present invention allows for the preparation of capsules over a wide range of functional groups and particle sizes in a single step process, making this method particularly suitable for industrial manufacturing processes, and more particularly for continuous industrial processes. By simply adjusting the monomer ratio, the technology can be easily tailored to the functional group to be encapsulated, and the physical properties can be easily tailored for various applications without significant changes to the process conditions. This provides a robust technology with considerable flexibility for industrialization.

[0033] The ring-opening polymerization of N-carboxyanhydrides has been reviewed by Cheng and Deming (Top. Curr. Chem., 310, 1-26 (2012)). Primary amines, and optionally secondary amines, are the most obvious initiators, and they are widely used to initiate ring-opening polymerization via nucleophilic initiation. Basic initiators can initiate ring-opening polymerization via an activated monomer mechanism, initiated by deprotonation of the NCA followed by ring-opening polymerization. When amine initiators are used, both mechanisms often proceed in parallel. Transition metal initiators are known to provide better control over the polymerization. The use of hexamethyldisilazane as an initiator has also been disclosed to provide better control over the polymerization.

[0034] In a further preferred embodiment, a mixture of N-carboxyanhydrides derived from different amino acids is used. In yet a further embodiment, a mixture of different chiralities is used, preferably a mixture of D- and L-amino acids in a ratio of 9 / 1 to 1 / 9. In another preferred embodiment, a mixture of different chiralities and different amino acids is used. Mixing D- and L-amino acids prevents the poly(amino acids) from forming secondary or tertiary structures, as peptides do in nature. The resulting polymer shell is therefore denser and more mechanically resistant.

[0035] In a particularly suitable interfacial ring-opening polymerization method for preparing capsules according to the present invention, N-carboxy-anhydride monomers and core materials are dissolved in a substantially water-immiscible solvent and emulsified in an aqueous solution containing a polymerization initiator. Upon emulsification and optional removal of the substantially water-immiscible solvent, ring-opening polymerization is initiated at the interface. As growth progresses, a poly(amino acid) shell forms at the organic-water interface, creating a core-shell structure that encapsulates the functional component or functional compound. The resulting polymer shell is mechanically strong and stable, allowing the capsules to be isolated from the liquid in which they were prepared.

[0036] The functional ingredient or functional formulation is preferably an organic compound. The organic compound is a hydrophobic compound, which has an octanol-water partition coefficient of log K ow This means that it is at least 0.3.

[0037] When the core material is liquid, dissolving it in a substantially water-immiscible solvent can be omitted, and the NCA can be dissolved directly in the core material. The capsules according to the present invention are particularly suitable for holding liquid core materials. Micelle-based capsules are not as suitable for encapsulating and holding liquid core materials. In fact, micelle-based shells are often too permeable compared to the polymer shells obtained by the encapsulation method of the present invention.

[0038] A particularly suitable interfacial ring-opening polymerization method comprises the steps of: a) dissolving a compound according to general structure 1 and an organic compound in a water-immiscible solvent; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step (a) in an aqueous liquid; and d) optionally evaporating the water-immiscible solvent; and e) polymerizing a compound according to general structure 1.

[0039] The particle size of the capsules of the present invention can be controlled by modifying the emulsification technique, the use of a co-emulsifier during emulsification and the ratio of co-emulsifier to shell and core, the nature of the co-emulsifier, the viscosity of the continuous or dispersed phase, the ratio of the continuous and dispersed phases, the nature of the core contents, and the nature of the shell monomer. High shear and ultrasonic techniques are particularly suitable as emulsification techniques. The particle size of the capsules of the present invention can be controlled by adjusting the shear in the high shear technique or by changing the power and amplitude during ultrasonic treatment.

[0040] Preferably, the organic compound has an octanol-water partition coefficient of log K ow is at least 0.3.

[0041] Difunctional or polyfunctional primary or secondary amines or mixtures thereof are particularly suitable initiators for the ring-opening polymerization of NCAs. The initiators are water-soluble and can be functionalized with additional hydrophilic functional groups. The additional hydrophilic functional groups are preferably selected from the group consisting of carboxylic acids or salts thereof, sulfonic acids or salts thereof, phosphonic acids or salts thereof, phosphoric esters or salts thereof, sulfuric esters or salts thereof, polyhydroxyl functional groups, poly(ethylene glycol), ammonium groups, sulfonium groups, and phosphonium groups.

[0042] The incorporation of poly(ethylene glycol) functional groups is particularly useful for imparting stealth properties to the capsules of the present invention when used as drug delivery systems in the human or animal body, which are necessary to avoid uptake by the reticuloendothelial system and to ensure that the drug is released in a controlled manner only at the site of need.

[0043] Exemplary initiators are provided in Table 2, but are not limited thereto. [Table 2-1] [Table 2-2]

[0044] In a further preferred embodiment, the shell composition further comprises a crosslinking agent. After biocompatibility and biodegradability, one of the most basic requirements for a capsule is stability in the medium in which the capsule must function or be stored, such as the human body in the case of a drug delivery system. If a system is not stable in that medium, this may result in a pre-burst release of the payload or release outside the target range. Improved stability leads to improved storage stability, and in the case of a drug delivery system, increased blood circulation time and improved bioavailability. By using a crosslinking agent, the stability and mechanical resistance of the capsule shell can be modified to meet the specifications of the system in which the capsule is to be used. Furthermore, crosslinking The use of a bridger allows for precise control of drug release when the capsules of the present invention are used for drug delivery purposes.

[0045] Any crosslinking agent known to crosslink amine-functionalized polymers can be used. Suitable crosslinking agents are selected from the group consisting of di- or multi-functional isocyanates, di- or multi-functional β-ketoesters, di- or multi-functional β-ketoamides, di- or multi-functional 1,3-diketones, di- or multi-functional epoxides or oxetanes, di- or multi-functional anhydrides, di- or multi-functional N-carboxyanhydrides, di- or multi-functional Michael reaction acceptors (e.g., acrylates, methacrylates, maleimides, vinyl sulfones, etc.), and di- or multi-functional five-membered cyclic carbonates.

[0046] Preferably, an additional emulsifier is used during the emulsification process. Typical emulsifiers are selected from polymers and surfactants. The polymers and surfactants can be co-reactive polymers or surfactants, such as those functionalized with primary and secondary amines, which act as both initiators and emulsifiers, resulting in so-called self-dispersing capsules. The surfactants can be anionic, nonionic, cationic, or zwitterionic. Hydroxyl-functionalized polymers are particularly suitable because they stabilize the polymer, and are preferably selected from polysaccharides and poly(vinyl alcohol) or poly(vinyl alcohol) copolymers or their derivatives.

[0047] B. Application Areas The encapsulation technology disclosed in this invention is particularly useful in the areas of personal care, pharmaceutical, nutritional, agricultural, and household applications, particularly for controlling the release of active ingredients or protecting them from hydrolysis or oxidation, such as the encapsulation of food ingredients, probiotics, fragrances and flavorings, pesticides, flame retardants, and last but not least, active pharmaceutical ingredients.

[0048] More generally, the ingredients in the capsule core preferably have an octanol-water partition coefficient of log K ow is at least 0.3, more preferably at least 0.5, and most preferably at least 1.

[0049] The octanol-water partition coefficient is defined as follows: K ow =C op / C w In the formula, C op and C w are the gL at 25°C in the concentrated octanol phase and concentrated water phase, respectively. -1 The compound concentration is determined taking into consideration the above.

[0050] The encapsulation technique according to the present invention is of particular interest for encapsulating substantially non-reactive hydrophobic ingredients, such as marine oils, vegetable oils, and essential oils. The technique is also of particular interest for encapsulating perfumes, flavorings, and insect repellents.

[0051] The encapsulation technique according to the present invention is further of particular interest for the encapsulation of active pharmaceutical ingredients and pesticides.

[0052] More particularly, the encapsulation technique is useful for encapsulating active pharmaceutical ingredients such as anticancer drugs, vaccines, peptides, proteins, sonosensitizers, drug carriers, genes, growth factors such as recombinant bone morphogenetic protein-2 (rhBMP-2), progesterone, procaine hydrochloride, bovine serum albumin, benzocaine, insulin, etc. The capsules of the present invention are particularly suitable for incorporation into pharmaceutical compositions for the treatment of cancer.

[0053] The capsules of the present invention may be used in cancer therapy, for example in the treatment of veterinary medicine as disclosed in EP 2891485A. The capsules can be used in arterial embolization, etc. In arterial embolization, these microparticles are used in a liquid form when inserted into the human body, but are preferably maintained in a solid state for stable storage. In another aspect of the invention, the capsules of the invention are suitable for the sonodynamic treatment of metastatic disease, micrometastatic disease, or the treatment of multiple primary tumors.

[0054] For use in any of the above-mentioned medical treatments, the capsule of the present invention is generally formulated into a pharmaceutical composition together with at least one pharmaceutically acceptable carrier or excipient.Such pharmaceutical compositions can be formulated using techniques well known in the art.The route of administration will depend on the intended use.Typically, the pharmaceutical composition will be administered systemically, and therefore can be provided in a form suitable for parenteral administration, for example, by intradermal injection, subcutaneous injection, intraperitoneal injection or intravenous injection.

[0055] Suitable pharmaceutical compositions include suspensions and solutions containing the capsules of the present invention together with one or more inert carriers or excipients.Suitable carriers include physiological saline, sterile water, phosphate buffered saline, and mixtures thereof.The composition may additionally contain other agents, such as emulsifiers, suspending agents, dispersing agents, solubilizers, stabilizers, buffers, wetting agents, preservatives, etc.The pharmaceutical composition can be sterilized by conventional sterilization techniques.The solution containing particles can be stabilized by adding agents such as viscosity adjusters, emulsifiers, solubilizers, etc.

[0056] Preferably, the pharmaceutical composition will be used in the form of an aqueous suspension or dispersion in which the capsule is contained in water or saline, e.g., phosphate buffered saline. The particles may be supplied in the form of a lyophilized powder that is reconstituted at the time of use, e.g., with water, saline, or phosphate buffered saline.

[0057] The capsules according to the present invention are particularly useful in consumer products such as shampoos, hair conditioners, hair rinses, hair refreshers, hair fixatives or styling aids, hair bleaches, hair dyes or colorants, soaps, body washes, cosmetics, all-purpose cleaners, bathroom cleaners, floor cleaners, window cleaners, toilet paper, paper towels, disposable wipes, diaper rash creams or balms, baby powders, diapers, bibs, baby wipes, oral care products, toothpastes, mouthwashes, toothpastes ... Whitening agents, denture adhesives, chewing gum, breath fresheners, oral dissolving strips, chewable candy, hard candy, hand sanitizers, anti-inflammatory balms, anti-inflammatory ointments, anti-inflammatory sprays, health care devices, dental floss, toothbrushes, tampons, feminine napkins, personal care products, sunscreen lotions, sunscreen sprays, wax-based deodorants, glycolic deodorants, soap-based deodorants, facial lotions, body lotions, hand lotions, body powders, shaving creams, bath salts soak, exfoliating scrub, foot cream, facial tissue, cleansing wipes, fabric care products, fabric softeners, fabric refreshers, ironing water, liquid laundry detergent, liquid dish detergent, automatic dishwasher detergent, unit dose tablets or capsules, scent booster, dryer sheet, fine fragrance, solid fragrance, powder foundation, liquid foundation, eye shadow, lipstick or lip balm, eau de toilette product, air freshener, carpet freshener, candle, room freshener, disinfectant, antiperspirant, roll-on product, and aerosol product. [Example]

[0058] C. Working Example C.1. Material All compounds are sourced from TCI Europe unless otherwise stated. L-phenylalanine N-carboxyanhydride, D-phenylalanine N-carboxyanhydride D,L-phenylalanine N-carboxyanhydride and D,L-phenylalanine N-carboxyanhydride were prepared according to the method described by Gabashvill et al. (Journal of Physical Chemistry B, 111(38), 11105-11110 (2007)) and Otake et al. (Angewandte Chemie, International Edition, 57(35), 11389-11393 (2018)). L-leucine N-carboxyanhydride, D-leucine N-carboxyanhydride, and D,L-leucine N-carboxyanhydride can be prepared according to standard methods as disclosed by Baars et al. (Organic Process Research and Development, 7(4), 509-513 (2003)). L-methionine N-carboxyanhydride and D,L-methionine N-carboxyanhydride can be prepared according to standard methods as disclosed by Verdie at al. (Chemistry-An Asian Journal, 6(9), 2382-2389 (2011)). γ-Benzyl-L-glutamic acid N-carboxyanhydride can be prepared according to standard methods as disclosed by Wang et al. (RSC Advances, 6(8), 6368-6377 (2016)). Glyceryl tricaprate was sourced from Esterchem. δ-Undecalactone was supplied by SAF Bulk Chemicals. Disflamol TKP is a mixture of cresyl and phenyl esters of phosphoric acid, supplied by Albright & Wilson. Mowiol 4 88 is a poly(vinyl alcohol) supplied by Kuraray. Marlon A365 is an anionic surfactant, supplied by Sasol Germany GMBH. Tris(2-aminoethyl)amine was supplied by TCI. Tracer-1 is a fluorescent marker (CASRN917102-92-2) having the following structural formula, and can be prepared according to the method disclosed in WO2008056506 (Konica Minolta Medical & Graphic Inc.). [ka] Crosslinker 1 is a trifunctional β-ketoester according to the following structural formula, which can be prepared as disclosed by Speisschaert et al. (Polymer, 172, 239-246 (2019)). [ka] Takenate D120N is a trifunctional isocyanate, supplied by Mitsui. Desmodur N75BA is a trifunctional isocyanate, supplied by Covestro. CATSURF-1 is a cationic surfactant according to the following structural formula, which can be prepared as disclosed in WO2018137993 (Agfa NV) as Surf-3: [ka]

[0059] C.2. Method Capsule particle size was measured using a Zetasizer™ Nano-S (Malvern Instruments, Goffin Meyvis).

[0060] C.3. Example 1 This example illustrates the encapsulation of various chemicals using interfacial ring-opening polymerization according to the present invention.

[0061] Synthesis of INVCAP-1 to INVCAP-3: Glyceryl Tricaprate Encapsulation (INVCAP-1): A first solution was prepared by dissolving 2.5 g of L-phenylalanine N-carboxyanhydride, 0.25 g of D-phenylalanine N-carboxyanhydride, 0.25 g of D,L-phenylalanine N-carboxyanhydride, 0.303 g of crosslinker 1, 2.8 g of glyceryl tricaprate, and 100 mg of Tracer-1 in 18 ml of ethyl acetate.

[0062] A second solution was prepared by dissolving 0.684 g of Mowiol 4 88, 0.256 g of Marlon A365, and 0.115 g of tris(2-aminoethyl)amine in 30 ml of water.

[0063] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 20 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0064] The average particle size was measured to be 1.01 μm.

[0065] Encapsulation of δ-undecalactone (INVCAP-2): A first solution was prepared by dissolving 2.5 g of L-phenylalanine N-carboxyanhydride, 0.25 g of D-phenylalanine N-carboxyanhydride, 0.25 g of D,L-phenylalanine N-carboxyanhydride, 0.303 g of crosslinker 1, 2.8 g of δ-undecalactone, and 100 mg of Tracer-1 in 18 ml of ethyl acetate.

[0066] A second solution was prepared by dissolving 0.684 g of Mowiol 4 88, 0.256 g of Marlon A365, and 0.115 g of tris(2-aminoethyl)amine in 30 ml of water.

[0067] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 20 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0068] The average particle size was measured to be 1.95 μm.

[0069] Disflamoll TKP encapsulation (INVCAP-3): A first solution was prepared by dissolving 2.5 g of L-phenylalanine N-carboxyanhydride, 0.25 g of D-phenylalanine N-carboxyanhydride, 0.25 g of D,L-phenylalanine N-carboxyanhydride, 0.303 g of crosslinker 1, 2.8 g of Disflamoll TKP, and 100 mg of Tracer-1 in 18 ml of ethyl acetate.

[0070] A second solution was prepared by dissolving 0.684 g of Mowiol 4 88, 0.256 g of Marlon A365, and 0.115 g of tris(2-aminoethyl)amine in 30 ml of water.

[0071] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 20 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0072] The average particle size was measured to be 1.25 μm.

[0073] Characterization of INVCAP-1 to INVCAP-3: Fluorescence photography: The capsules of the present invention, INVCAP-1 to INVCAP-3, were analyzed using an optical microscope equipped with a UV lamp emitting UV light at a wavelength of 365 nm at 63x magnification. First, a visual image of each sample was taken. For the second image, the capsule dispersion was exposed to UV light, and a fluorescent image was taken. An overlay of the visual and fluorescent images was then created. The overlay revealed that for all capsules, the fluorescent image perfectly matched the visual image of the particle, clearly demonstrating that the chemical substance was encapsulated. Centrifugation:

[0074] The capsules of the present invention, INVCAP-1 through INVCAP-3, were isolated by centrifugation at 4500 RPM for 1 hour in a Thermo Scientific SL8 centrifuge. Both the capsules and the supernatant were isolated and analyzed for the presence of unencapsulated compounds and fluorescence. No unencapsulated compounds could be detected in any of the samples. Fluorescence could only be detected in the capsules themselves, again clearly demonstrating that the chemicals were encapsulated.

[0075] The isolated capsules were redispersed in water and both visual and fluorescent images were taken. Again, the visual and fluorescent images of INVCAP-1 to INVCAP-3 were in perfect agreement.

[0076] INVCAP-1 to INVCAP-3 were dried to obtain powders. No evidence of encapsulated chemicals was found outside the capsules. The powders could be easily redispersed in water.

[0077] C.4. Example 2 This example illustrates that a range of amino acids can be used in interfacial ring-opening polymerization to prepare encapsulates according to the present invention.

[0078] (J) Capsule shells containing leucine as a monomer (INVCAP-4 to INVCAP-7) Synthesis of INVCAP-4 3 g of L-leucine N-carboxyanhydride was dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.303 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.28 g of glyceryl tricaprate were added.

[0079] A second solution was prepared by dissolving 0.684 g of Mowiol 4 88, 0.256 g of Marlon A365, and 0.115 g of tris(2-aminoethyl)amine in 30 ml of water.

[0080] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 20 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0081] The average particle size was measured to be 0.86 μm.

[0082] Synthesis of INVCAP-5 1.5 g of L-leucine N-carboxyanhydride and 1.5 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.336 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.59 g of glyceryl tricaprate were added.

[0083] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0084] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0085] The average particle size was measured to be 0.574 μm.

[0086] Synthesis of INVCAP-6: 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.75 g of L-phenylalanine N-carboxyanhydride, and 0.75 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.336 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.59 g of glyceryl tricaprate were added.

[0087] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0088] Mix using Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes. The first solution was added to the second solution while maintaining the temperature of the emulsion at 20°C to 30°C. 10 ml of water was added, and the mixture was then evaporated under reduced pressure to 25 g. Polymerization was continued at room temperature for 24 hours.

[0089] The average particle size was measured to be 0.569 μm.

[0090] Synthesis of INCAP-7: 1.5 g of L-leucine N-carboxyanhydride and 1.5 g of L-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.336 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.59 g of glyceryl tricaprate were added.

[0091] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0092] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0093] The average particle size was measured to be 0.465 μm.

[0094] (J) Capsule shells containing methionine as a monomer (INVCAP-8 to INVCAP-11) Synthesis of INVCAP-8: 3 g of D,L-methionine N-carboxyanhydride was dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.331 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.33 g of glyceryl tricaprate were added.

[0095] A second solution was prepared by dissolving 0.69 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.125 g of tris(2-aminoethyl)amine in 30 ml of water.

[0096] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0097] Synthesis of INVCAP-9: 1.5 g of D,L-methionine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, and 0.75 g of D-leucine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.35 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.32 g of glyceryl tricaprate were added.

[0098] A second solution was prepared by dissolving 0.696 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.132 g of tris(2-aminoethyl)amine in 30 ml of water.

[0099] Mix using Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes. The first solution was added to the second solution while maintaining the temperature of the emulsion at 20°C to 30°C. 10 ml of water was added, and the mixture was then evaporated under reduced pressure to 25 g. Polymerization was continued at room temperature for 24 hours.

[0100] Synthesis of INVCAP-10: 0.6 g of D,L-methionine N-carboxyanhydride, 0.6 g of L-leucine N-carboxyanhydride, 0.6 g of D-leucine N-carboxyanhydride, 0.6 g of L-phenylalanine N-carboxyanhydride, and 0.6 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.335 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.32 g of glyceryl tricaprate were added.

[0101] A second solution was prepared by dissolving 0.696 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.132 g of tris(2-aminoethyl)amine in 30 ml of water.

[0102] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0103] Synthesis of INVCAP-11: 0.6 g of L-methionine N-carboxyanhydride, 0.6 g of L-leucine N-carboxyanhydride, 0.6 g of D-leucine N-carboxyanhydride, 0.6 g of L-phenylalanine N-carboxyanhydride, and 0.6 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.335 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.32 g of glyceryl tricaprate were added.

[0104] A second solution was prepared by dissolving 0.696 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.132 g of tris(2-aminoethyl)amine in 30 ml of water.

[0105] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0106] (J) Capsule shells containing γ-benzyl glutamic acid as a monomer (INVCAP-12 and INVCAP-13) Synthesis of INVCAP-12: 1.5 g of L-γ-benzylglutamic acid N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, and 0.75 g of D-leucine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.294 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.26 g of glyceryl tricaprate were added.

[0107] A second solution was prepared by dissolving 0.68 g of Mowiol 4 88, 0.255 g of Marlon A365, and 0.111 g of tris(2-aminoethyl)amine in 30 ml of water.

[0108] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0109] Synthesis of INVCAP-13: 0.6 g of L-γ-benzylglutamic acid N-carboxyanhydride, 0.6 g of L-leucine N-carboxyanhydride, 0.6 g of D-leucine N-carboxyanhydride, 0.6 g of L-phenylalanine N-carboxyanhydride, and 0.6 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.313 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.32 g of glyceryl tricaprate were added.

[0110] A second solution was prepared by dissolving 0.68 g of Mowiol 4 88, 0.255 g of Marlon A365, and 0.118 g of tris(2-aminoethyl)amine in 30 ml of water.

[0111] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 25 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0112] Characterization of INVCAP-4 to INVCAP-13: The capsules of the present invention, INVCAP-4 to INVCAP-13, were characterized by fluorography and centrifugation as disclosed in Example 1. Based on this analysis, it was demonstrated that glyceryl tricaprate was completely encapsulated in all cases.

[0113] C.5. Example 3 This example illustrates the use of different cross-linking agents in the synthesis of capsules according to the present invention. Trifunctional isocyanates were selected as cross-linking agents in the synthesis of INVCAP-14 and INVCAP-15.

[0114] Synthesis of INVCAP-14: 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.75 g of L-phenylalanine N-carboxyanhydride, and 0.75 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.831 g of Takenate D120N, 0.1 g of Tracer-1, and 2.59 g of glyceryl tricaprate were added.

[0115] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0116] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0117] Synthesis of INVCAP-15: 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.75 g of L-phenylalanine N-carboxyanhydride, and 0.75 g of D-phenylalanine N-carboxyanhydride were dissolved in 18 ml of ethyl acetate. The solution was filtered through a 1.7 micron filter. 0.555 g of Desmodur N75BA, 0.1 g of Tracer-1, and 2.59 g of glyceryl tricaprate were added.

[0118] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0119] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0120] Characterization of INVCAP-14 and INVCAP-15: The capsules of the present invention, INVCAP-14 to INVCAP-15, were characterized by fluorography and centrifugation as disclosed in Example 1. Based on this analysis, it was demonstrated that glyceryl tricaprate was completely encapsulated in all cases.

[0121] C.6. Example 4: This example illustrates the applicability of various colloidal stabilization mechanisms in the synthesis of capsules according to the present invention by replacing the nonionic polymeric stabilizer and anionic surfactant used in the previous examples with a cationic co-reactive surfactant in the capsule synthesis, as illustrated by the synthesis of cationic self-dispersing capsules.

[0122] Synthesis of INVCAP-16: 0.75 g of L-leucine N-carboxyanhydride, 0.75 g of D-leucine N-carboxyanhydride, 0.75 g of L-phenylalanine N-carboxyanhydride, and 0.75 g of D-phenylalanine N-carboxyanhydride were dissolved in 25 ml of ethyl acetate, and 0.336 g of Crosslinker 1, 0.1 g of Tracer-1, and 2.50 g of glyceryl tricaprate were added.

[0123] A second solution was prepared by dissolving 1.01 g of CATSURF-1 in 30 ml of water.

[0124] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the emulsion temperature between 20°C and 30°C. 10 ml of water was added, and the mixture was then evaporated to 30 g under reduced pressure. Polymerization was allowed to continue at room temperature for 24 hours.

[0125] INVCAP-16 Characterization: The capsules of the present invention, INVCAP-16, were characterized by fluorography and centrifugation as disclosed in Example 1. Based on this analysis, it was demonstrated that glyceryl tricaprate was completely encapsulated in INVCAP-16.

[0126] C.7. Example 5 This example illustrates the option of isolating capsules according to the present invention using lyophilization.

[0127] A first solution was prepared by dissolving 1.5 g of D,L-phenylalanine N-carboxyanhydride, 0.75 g of L-leucine N-carboxyanhydride, and 0.75 g of D-leucine N-carboxyanhydride in 18 ml of ethyl acetate. 0.336 g of Crosslinker 1, 2.309 g of glyceryl tricaprate, and 0.1 g of glyceryl tricaprate were added.

[0128] A second solution was prepared by dissolving 0.692 g of Mowiol 4 88, 0.259 g of Marlon A365, and 0.127 g of tris(2-aminoethyl)amine in 30 ml of water.

[0129] The first solution was added to the second solution while mixing with an Ultra Turrax T25 (IKA) at 6000 rpm for 5 minutes, while maintaining the temperature of the emulsion between 20°C and 30°C. The ethyl acetate was removed under reduced pressure, and the weight of the dispersion was adjusted to 30 g. Polymerization was continued at room temperature for 24 hours.

[0130] Capsules were isolated by freeze-drying. Capsule redispersibility was assessed by redispersing a sample of the isolated capsules in water using sonication. Sonication was performed using a Sona Vibra Cell at 19-21 watts and an amplitude of 100 for 5 seconds. The degree of dispersion was assessed using an optical microscope at 63x magnification, and the images were compared with microscopic analysis of the original dispersion obtained after synthesis. Both images showed the same degree of dispersion. No oversized or additional clusters could be detected after redispersion.

Claims

1. A capsule consisting of a polymeric shell surrounding a core, said core comprising an organic compound, said polymeric shell comprising a poly(amino acid) and obtainable by interfacial polymerization of N-carboxy-anhydride monomers according to general structure I: 【Chemical 1】 During the ceremony, n represents 0 or 1; R １ , R ２ , and R ３ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted alkaryl groups, and substituted or unsubstituted aryl or heteroaryl groups; R １ , R ２ , and R ３ represents the atoms necessary to form a five- to eight-membered ring, The capsule.

2. The organic compound has a log K ｏｗ 2. The capsule of claim 1, having an octanol-water partition coefficient, expressed as a function of 0.3 or greater.

3. 10. The capsule of any one of the preceding claims, wherein the organic compound is selected from the group consisting of marine oils, vegetable oils, essential oils, fragrances, flavorings, insect repellents, flame retardants, active pharmaceutical ingredients, and pesticides.

4. 10. The capsule of any one of the preceding claims, further comprising an average particle size of 0.07 μm to 5 μm.

5. 10. The capsule of any one of the preceding claims, wherein the polymer shell comprises a cross-linking agent.

6. 10. The capsule of any one of the preceding claims, wherein the polymeric shell comprises a dispersing group selected from the group consisting of a carboxylic acid or its salt, a sulfonic acid or its salt, a phosphoric ester or its salt, a phosphonic acid or its salt, a protonated amine, a protonated nitrogen-containing heteroaromatic compound, a quaternized tertiary amine, an N-quaternized heteroaromatic group, a sulfonium, and a phosphonium.

7. 10. The capsule of claim 1, wherein the poly(amino acids) comprise L-amino acids and D-amino acids.

8. 4. The capsule of claim 3, wherein the organic compound is selected from the group consisting of an anti-cancer drug, a vaccine, a peptide, a protein, and a sonosensitizer.

9. 10. A pharmaceutical composition comprising the capsule of claim 8 and a pharmaceutical carrier or excipient.

10. 8. Consumer products comprising capsules as defined in claims 1 to 7, including shampoos, hair conditioners, hair rinses, hair refreshers, hair fixatives or styling aids, hair bleaches, hair dyes or colorants, soaps, body washes, cosmetics, all-purpose cleaners, bathroom cleaners, floor cleaners, window cleaners, toilet paper, paper towels, disposable wipes, diaper rash creams or balms, baby powders, diapers, bibs, baby wipes, oral care products, toothpastes, mouthwashes, teeth bleaching anti-inflammatory balm, anti-inflammatory ointment, anti-inflammatory spray, health care device, dental floss, toothbrush, tampon, feminine napkin, personal care product, sunscreen lotion, sunscreen spray, wax-based deodorant, glycol-based deodorant, soap-based deodorant, facial lotion, body lotion, hand lotion, body powder, shaving cream, bath soak, exfoliating scrub, foot cream, facial tissue, cleansing wipes, fabric care product, fabric softener, fabric refresher, ironing water, liquid laundry detergent, liquid dish detergent, automatic dishwasher detergent, unit dose tablet or capsule, fragrance booster), dryer sheets, fine fragrances, solid fragrances, powder foundations, liquid foundations, eye shadows, lipsticks or lip balms, eau de toilette products, air fresheners, carpet fresheners, candles, room fresheners, disinfectants, antiperspirants, roll-on products, and aerosol products.

11. 9. A method for preparing a capsule as defined in any one of claims 1 to 8, comprising the following steps: a) dissolving an N-carboxy-anhydride monomer according to general structure 1 and an organic compound in a water-immiscible solvent; and b) dissolving a polymerization initiator in an aqueous liquid; and c) emulsifying the solution obtained in step (a) in the aqueous liquid; and d) optionally evaporating the water-immiscible solvent; and e) polymerizing said N-carboxy-anhydride monomer according to general structure 1; The method comprising:

12. The organic compound has an octanol-water partition coefficient of log K ｏｗ 12. The method for preparing a capsule according to claim 11, wherein the β-glucan content is 0.3 or more.

13. 13. The method for preparing capsules according to claims 11 to 12, wherein a surfactant or a hydrophilic polymer is added to the aqueous liquid.

14. 14. The method for preparing a capsule according to claims 11 to 13, wherein a cross-linking agent is added to the water-immiscible solvent in step (a).

15. 15. The method for preparing capsules according to claims 11 to 14, wherein the polymerization initiator is a di- or polyfunctional primary or secondary amine.

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