R² is hydrogen or a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 3 to 18 carbon atoms, and the minimum total number of carbon atoms in R¹ and R² is 6, and the maximum total number of carbon atoms in R¹ and R²is 18; and wherein, in formula (II),

R³ is a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 4 to 11 carbon atoms, and

R⁴ is a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 4 to 11 carbon atoms.

7. A composition comprising

(i) a hydrogel, and

(ii) an oil-in-water emulsion entrapped in the hydrogel, wherein an active agent is incorporated into the oil droplets dispersed in the oil-in-water emulsion, and wherein the oil droplets comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

wherein, in formula (I),

R² is hydrogen or a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 3 to 18 carbon atoms, and the minimum total number of carbon atoms in R¹ and R² is 6, and the maximum total number of carbon atoms in R¹ and R² is 18; and wherein, in formula (II),

R³ is a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 4 to 11 carbon atoms, and R⁴ is a hydrocarbon group, preferably an aliphatic hydrocarbon group, having 4 to 11 carbon atoms.

8. A composition comprising a mixture of

(i) a dried hydrogel, and

(ii) oil droplets, wherein an active agent is incorporated into the oil droplets, and wherein the oil droplets comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

(II), wherein, in formula (I),

9. The composition in accordance with item 8, wherein the dried hydrogel is comprised in the form of a powder. 10. The composition in accordance with item 8 or 9, which is obtainable by removing water from the composition in accordance with item 7, more preferably by removing water by freeze-drying the composition in accordance with item 7.

11. The composition in accordance with any of items 6 to 10, wherein R¹ is C6-18 alkyl or C6-18 alkenyl, and R² is hydrogen.

12. The composition in accordance with item any of items 6 to 11, wherein R³ and R⁴ are independently C4-11 alkyl or C4-11 alkenyl.

13. The composition in accordance with any of items 1 to 12, wherein the hydrolyzable oil accounts for 70 wt% or more, more preferably 80 wt% or more, and still more preferably 90 wt% or more, of the total weight of the oil in the oil droplets as 100 wt%.

14. The composition in accordance with any of items 1 to 13, wherein the oil in the oil droplets consists of the hydrolyzable oil.

15. The composition in accordance with any of items 1 to 14, wherein the active agent incorporated into the oil droplets is an active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 niM.

16. The composition in accordance with any of items 1 to 15, which is a pharmaceutical composition having a pharmaceutically active agent incorporated into the oil droplets.

17. The composition in accordance with item 16, wherein the pharmaceutically active agent is a BCS class II drug or a BCS class IV drug.

18. The composition in accordance with any of items 1 to 16, which is a pharmaceutical composition, wherein the active agent incorporated into the oil droplets is selected from a peptide, DNA, modified DNA, RNA, modified RNA, dsRNA, siRNA, miRNA, and an antisense oligonucleotide.

19. The composition in accordance with any of items 1 to 18, wherein the hydrogel is a non-charged hydrogel. 20. The composition in accordance with any of items 1 to 19, wherein the hydrogel comprises a polysaccharide or a polysaccharide derivative with hydroxyl groups of the polysaccharide being esterified.

21. The composition in accordance with any of items 1 to 20, wherein the hydrogel is selected from an agar gel, a glycogen gel and a cellulose gel.

22. The composition in accordance with any of items 1, 5 to 7 and 11 to 21, which is the composition comprising a hydrogel and an oil-in-water emulsion entrapped in the hydrogel, and wherein the aqueous phase of the oil-in-water emulsion comprises a buffer which adjusts the pH of the aqueous phase to a value of 4 to 10.

23. A composition which is obtainable by removing water from the composition comprising a hydrogel and an oil-in-water emulsion entrapped in the hydrogel in accordance with any of items 1, 5 to 7 and 11 to 22, more preferably by removing water by freeze-drying the composition comprising a hydrogel and an oil-in-water emulsion entrapped in the hydrogel in accordance with any of items 1 , 5 to 7 and 11 to 22.

24. A process for the preparation of a composition in accordance with item 1, which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, and mixing the oil-in-water emulsion with a hydrogel, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil which undergoes hydrolysis with a first-order rate constant of hydrolysis between 180 hr¹ and 0.18 hr¹ and which shows a solubility in water at a pH of 7.4 and a temperature of the water of 37°C in the range of 100 nM to 10 mM.

25. A process for the preparation of a composition in accordance with any of items 2 to 4 or 23, which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, mixing the oil-in-water emulsion with a hydrogel, and freeze-drying the obtained mixture, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil which undergoes hydrolysis with a first-order rate constant of hydrolysis between 180 hr¹ and 0.18 hr¹ and which shows a solubility in water at a pH of 7.4 and a temperature of the water of 37°C in the range of 100 nM to 10 mM.

26. The process in accordance with item 25, wherein the mixture of the hydrogel and the oil-in-water emulsion is surrounded by a membrane during freeze-drying.

27. The process in accordance with any of items 24 to 26, wherein the oil-in-water emulsion is mixed with a liquefied hydrogel, followed by the gelation of the hydrogel.

28. The process in accordance with any of items 24 to 27, wherein the hydrolyzable oil is a compound is selected from an ester of a carboxylic acid, an amide of a carboxylic acid, an anhydride of a carboxylic acid, and combinations thereof.

29. The process in accordance with any of items 24 to 27, wherein the hydrolyzable oil is a compound of formula (I) or a compound of formula (II)

wherein, in formula (I),

30. A process for the preparation of a composition in accordance with item 7, which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, and mixing the oil-in-water emulsion with a hydrogel, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

(ii), wherein, in formula (I),

31. A process for the preparation of a composition in accordance with any of items 8 to

10 or 23, which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, mixing the oil-in-water emulsion with a hydrogel, and freeze-drying the obtained mixture, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

(II) wherein, in formula (I),

32. The process in accordance with item 31, wherein the mixture of the hydrogel and the oil-in-water emulsion is surrounded by a membrane during freeze-drying.

33. The process in accordance with any of items 31 or 32, wherein the oil-in-water emulsion is mixed with a liquefied hydrogel, followed by the gelation of the hydrogel. 34. The process in accordance with any of items 29 to 33, wherein R¹ is C6-18 alkyl or C6-18 alkenyl, and R² is hydrogen.

35. The process in accordance with any of items 29 to 33, wherein R³ and R⁴ are independently C4-11 alkyl or C4-11 alkenyl.

36. The process in accordance with any of items 24 to 35, wherein the hydrolyzable oil accounts for 70 wt% or more, more preferably 80 wt% or more, and still more preferably 90 wt% or more, of the total weight of the oil in the oil droplets as 100 wt%.

37. The process in accordance with any of items 24 to 36, wherein the oil in the oil droplets consists of the hydrolyzable oil.

38. The process in accordance with any of items 24 to 37, wherein the active agent incorporated into the oil droplets is an active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 mM.

39. The process in accordance with any of items 24 to 38, wherein the obtained composition is a pharmaceutical composition, wherein the active agent incorporated into the oil droplets is a pharmaceutically active agent.

40. The process in accordance with item 39, wherein the pharmaceutically active agent is a BCS class II drug or a BCS class IV drug.

41. The process in accordance with any of items 24 to 40, wherein the obtained composition is a pharmaceutical composition, wherein the active agent incorporated into the oil droplets is selected from a peptide, DNA, modified DNA, RNA, modified RNA, dsRNA, siRNA, miRNA, and an antisense oligonucleotide.

42. The process in accordance with any of items 24 to 41 , wherein the hydrogel is a non- charged hydrogel.

43. The process in accordance with any of items 24 to 42, wherein the hydrogel comprises a polysaccharide or a polysaccharide derivative wherein hydroxyl groups are esterified. 44. The process in accordance with any of items 24 to 43, wherein the hydrogel is selected from an agar gel, a glycogen gel and a cellulose gel.

45. The process in accordance with any of items 24 to 44, wherein the aqueous phase of the oil-in-water emulsion comprises a buffer which adjusts the pH of the aqueous phase to a value of 4 to 10.

46. The composition in accordance with any of items 16 to 23 having a pharmaceutically active agent incorporated into the oil droplets for use in medicine.

47. The composition in accordance with any of items 16 to 23 having a pharmaceutically active agent incorporated into the oil droplets for use in treatment or prevention of a medical condition to be treated or prevented by the controlled release of the pharmaceutically active agent.

48. The composition in accordance with item 46 or 47, wherein the composition is adapted for oral administration.

49. The composition in accordance with any of items 46 to 48, wherein the composition is contained in a pharmaceutical capsule.

50. The composition in accordance with item 46 or 47, wherein the composition is adapted for administration via subcutaneous injection.

51. A method of treating or preventing a medical condition, said method comprising administering an effective amount of the composition in accordance with any of items 16 to 23, having a pharmaceutically active agent incorporated into the oil droplets, to a patient in need thereof.

52. The method in accordance with item 51, wherein the composition is administered orally.

53. The method in accordance with item 51 or 52, wherein the composition is contained in a pharmaceutical capsule.

54. The method in accordance with item 51, wherein the composition is administrated via subcutaneous injection. As explained above, the present invention relates to compositions comprising a hydrogel and oil droplets associated with the hydrogel, wherein an active agent is incorporated into the oil droplets. The oil droplets comprise a hydrolyzable oil as defined herein which undergoes hydrolysis with a first-order rate constant of hydrolysis between 180 hr¹ and 0.18 hr¹ and which shows a solubility in water at a pH of 7.4 and a temperature of the water of 37°C in the range of 100 nM to 10 mM. In the emulsion composition of the first aspect, the oil droplets are dispersed as the oil phase in an oil-in-water emulsion, and the oil-in-water emulsion is entrapped by the hydrogel. In the dry composition of the second aspect, the oil droplets are comprised as a mixture with a dried hydrogel. It will be understood that the following explanation, and in particular the explanation regarding the hydrogel, the oil droplets and the active agent incorporated therein, applies to all aspects of the invention, unless indicated to the contrary.

The oil droplets comprise a hydrolyzable oil which undergoes hydrolysis with a first-order rate constant of hydrolysis between 180 hr¹ and 0.18 hr¹ and which shows a solubility in water at a pH of 7.4 and a temperature of the water of 37°C in the range of 100 nM to 10 mM.

As implied by the term “oil”, the oil droplets and the hydrolyzable oil contained therein form a liquid phase in the compositions in accordance with the invention, e.g. when the compositions are held or prepared at temperatures of 20°C or more. This applies both for the emulsion composition and for the dry composition, although the latter typically appears dry and can be handled as a dry substance due to the presence of the dried hydrogel mixed with the oil droplets.

Preferably, the hydrolyzable oil is a compound which can be hydrolyzed to yield one or more reaction products in the hydrolysis reaction which have a water solubility which is higher than that of the starting compound which is subjected to hydrolysis, e.g. higher than 10 mM at a pH of 7.4 and a temperature of the water of 37°C. This is typically the case e.g. for and ester of a carboxylic acid, an amide of a carboxylic acid, or an anhydride of a carboxylic acid, which yield a carboxylate compound when they are hydrolyzed.

A single compound may be used as hydrolyzable oil, or two or more compounds fulfilling the above requirements may be used in combination as hydrolyzable oils. In order to achieve a constant release rate of the active agent over the lifetime of the emulsion in a composition in accordance with the invention, it would be suitable to use a single type of hydrolyzable oil therein. For the skilled person, it will be unproblematic to select a suitable hydrolyzable oil for the compositions in accordance with the invention in line with the above criteria. If necessary, e.g. if literature data are not available for a compound considered for use as a hydrolyzable oil, the rate constant of hydrolysis can be conveniently determined by completely dissolving the hydrolyzable oil into an aqueous buffered solution at pH 7.4 and 37°C, measuring the evolution of the concentration of the hydrolyzable oil in the aqueous phase by HPLC, and calculating the rate constant of hydrolysis on the basis of the observed changes in the concentration. Likewise, the solubility of the hydrolyzable oil in water can be determined by dispersing the hydrolyzable oil as oil droplets into an aqueous buffered solution at pH 7.4 and 37°C, and, once all droplets have dissolved, measuring the concentration of the hydrolyzable oil in the buffered solution by HPLC as the concentration indicating the solubility of the oil under consideration.

Preferably, the hydrolyzable oil is a compound selected from an ester of a carboxylic acid, an amide of a carboxylic acid, an anhydride of a carboxylic acid, and combinations thereof, taking into account the above requirements. Depending on their structure these carboxylic acid derivatives can be susceptible to hydrolysis in water without the need for harsh (e.g. very acidic or very basic) conditions. Among them, anhydrides of carboxylic acids are particularly preferred.

As a hydrolyzable oil which meets the requirements set forth above with respect to solubility and hydrolyzability, particularly preferred are compounds selected from a compound of formula (I) and a compound of formula (II)

(II) which may be used singly or in combination as the hydrolyzable oil in the oil droplets of the compositions in accordance with the invention. In formula (I) above,

R¹ is a hydrocarbon group having 3 to 18 carbon atoms,

R² is hydrogen or a hydrocarbon group having 3 to 18 carbon atoms, and the minimum total number of carbon atoms in R¹ and R² is 6, and the maximum total number of carbon atoms in R¹ and R² is 18. As will be understood, the total number of carbon atoms, which needs to be 6 or more and 18 or less represents the sum of the number of carbon atoms in R¹ and R². As a hydrocarbon group, an aliphatic hydrocarbon group is preferred, which may be saturated or may contain one or more, e.g. one, two or three, C-C double bonds. More preferred as the hydrocarbon group is an alkyl or an alkenyl group.

Among the options available for R², it is preferred that R² is a hydrogen atom. In this case, it follows from the above definition that R¹ is a hydrocarbon group having 6 to 18 carbon atoms, for which the above preferred options likewise apply. Thus, it is particularly preferred for the compounds of formula (I) that R¹ is C6-18 alkyl or C6-18 alkenyl, and R² is hydrogen.

In formula (II) above,

R³ is a hydrocarbon group having 4 to 11 carbon atoms, and

R⁴ is a hydrocarbon group having 4 to 11 carbon atoms. As a hydrocarbon group, an aliphatic hydrocarbon group is preferred, which may be saturated or may contain one or more, e.g. one, two or three, C-C double bonds. More preferred as the hydrocarbon group is an alkyl or an alkenyl group. Thus, it is particularly preferred for the compounds of formula (II) that R³ and R⁴ are independently C4-11 alkyl or C4-11 alkenyl.

Preferred examples for the hydrolyzable oil to be used in the oil droplets of the composition in accordance with the invention are 2-decen-1-ylsuccinic anhydride, 2-dodecen-1-ylsuccinic anhydride, and 2-tetradecen-1-ylsuccinic anhydride, as well as hexanoic anhydride, heptanoic anhydride, and octanoic anhydride.

In order to provide a favorable hydrolyzability for the oil droplets in the compositions of the present invention, the hydrolyzable oil preferably accounts for 70 wt% or more, more preferably 80 wt% or more, and still more preferably 90 wt% or more, of the total weight of the oil in the oil droplets as 100 wt%. The weight of the oil corresponds to the weight of the oil droplets minus the weight of the active agent incorporated into the oil droplets. Most preferably, the oil in the oil droplets consists of the hydrolyzable oil. The active agent incorporated into the oil droplets is generally an active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 mM. The active agent is dissolved or dispersed, preferably dissolved, in the oil droplets in the composition in accordance with the invention.

In view of the advantages that the compositions in accordance with the present invention can provide with regard to the controlled release of an active agent under in vivo conditions in the body, the active agent incorporated into the oil droplets is preferably a pharmaceutically active agent, i.e. an agent which is suitable for the therapeutic or the prophylactic treatment of the human or animal body. However, the compositions can also be used to achieve a controlled release of active agents in other environments where water is present, e.g. of plant protecting agent, such as herbicides, fungicides or pesticides, which may be released into the soil.

As examples for pharmaceutically active agents for which the compositions of the invention are advantageous, reference can be made to the active agents with a low solubility in water, i.e. preferably with a solubility of less than 1 mM as mentioned above, classified in BCS class II and in BCS class IV, among which BCS class II active agents are preferred. As specific examples, Nitrendipine, Nimesulide, Mebendazole, and Glyburide may be mentioned.

As further types of pharmaceutically active agents suitable for use in the compositions in accordance with the present invention, pharmaceutically active agents selected from a peptide, DNA, modified DNA, RNA, modified RNA, dsRNA, siRNA, miRNA, and an antisense oligonucleotide. For example, nucleic acids, i.e. DNA or RNA, modified with hydrophobic moieties may be incorporated into the oil droplets of the compositions in accordance with the invention.

The oil droplets in the composition in accordance with the invention may contain a single active agent, or combinations of active agents, e.g. two or three types. It is not necessary that the oil droplets contain other components in addition to the oil and the active agent, i.e. the oil droplets may consist of the oil and the active agent.

In the emulsion composition of the present invention, the combination of a first order rate constant of hydrolysis and a limited solubility results in a linear decay of the concentration of the hydrolyzable oil. Without wishing to be bound by theory, it is noted that the reaction rate r of the hydrolysis is given by the rate constant k multiplied by the concentration c of hydrolyzable oil (equation 1). Because of the droplet formation by the oil molecules, the oil molecules are protected from water and thus from hydrolysis. Only the oil molecules that remain in solution are susceptible to hydrolysis. Because the concentration of oil molecules that remains in solution is constant and equal to the solubility of the hydrolyzable oil, the hydrolysis rate is also constant (zero-order kinetics). As an example, the solubility of C10-SA is roughly 0.03 mM. Only that fraction is susceptible to hydrolysis. r = k c (C₁₀SA) = k S (C₁₀5A) = constant

Equation 1: Reaction rate of hydrolysis of the hydrolyzable oil in solution.

The consequence of the linear decay of the oil molecules is that the total volume of the oil droplets ( V₀u) also decreases constantly over time. In other words, the reservoir for the active agent ( i.e the oil droplets) decomposes with a constant rate. Thus, the constant decomposition of the of oil droplets can be exploited in the present invention to release hydrophobic drugs with a constant rate. The idea is that the active agent partitions into the metastable oil droplets. Due to the partition coefficient P (equation 2), the incorporation of the active agent, e.g. a drug, c(drug₀n) is directly dependent on the oil volume of the emulsion. Consequently, the concentration drug in the aqueous phase of the emulsion c(drug_aq) increases linearly with time while the volume of the oil droplets decreases.

Equation 2: Definition of the partition coefficient P.

Preferred compositions in accordance with the invention and in line with the above information can be defined as: a) a composition comprising

(i) a hydrogel, and

(ii) an oil-in-water emulsion entrapped in the hydrogel, wherein a pharmaceutically active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 mM is incorporated into the oil droplets dispersed in the oil-in-water emulsion, and wherein the oil droplets comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

wherein, in formula (I),

R¹ is a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 3 to 18 carbon atoms,

R² is hydrogen or a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 3 to 18 carbon atoms, and the minimum total number of carbon atoms in R¹ and R² is 6, and the maximum total number of carbon atoms in R¹ and R² is 18; and wherein, in formula (II),

R³ is a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 4 to 11 carbon atoms, and R⁴ is a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 4 to 11 carbon atoms; and b) a composition comprising a mixture of

(i) a dried hydrogel, and

(ii) oil droplets, wherein a pharmaceutically active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 mM is incorporated into the oil droplets dispersed in the oil-in-water emulsion, and wherein the oil droplets comprise a hydrolyzable oil which is a compound of formula (I) or a compound of formula (II)

wherein, in formula (I),

R³ is a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 4 to 11 carbon atoms, and R⁴ is a hydrocarbon group, preferably an aliphatic hydrocarbon group and still more preferably an alkyl or alkenyl group, having 4 to 11 carbon atoms.

The concentration of the active agent in the emulsion composition preferably ranges from 20 pM to 10 mM, more preferably from 20 mM to 1 mM, and still more preferably from 50 to 100 pM, based on the total volume of the composition including the hydrogel and the oil-in-water emulsion (at 20°C).

In the emulsion composition in accordance with the invention comprising a hydrogel and an oil-in-water emulsion entrapped in the hydrogel, the oil droplets are preferably contained in an amount/at a concentration of 1 to 100 mM, more preferably from 5 to 15 mM, based on the total volume of the composition comprising the hydrogel and the oil-in-water emulsion (at 20°C).

As regards the hydrogel to be used in the compositions in accordance with the invention, no particular restrictions apply. However, preferably a non-charged hydrogel is used. In terms of the hydrophilic polymer structure contained in the hydrogel, a hydrogel comprising a polysaccharide or a polysaccharide derivative is preferably used, with hydroxyl groups of the polysaccharide being esterified in the polysaccharide derivative. As examples of such hydrogels, an agar gel, a glycogen gel and a cellulose gel may be mentioned.

As noted above, the oil-in-water emulsion of the emulsion composition in accordance with the first aspect of the present invention is entrapped in the hydrogel of the emulsion composition, so that the resulting structure may also be referred to as an emulgel. As will be appreciated by the skilled reader, the pores formed by the network structure of a hydrogel are able to accommodate large volumes of liquids (including emulsions).

Concentrations of the hydrogel forming polymer in the emulsion compositions in accordance with the invention can be suitably selected e.g. with a view to the type of gel used, and the desired consistency of the emulsion composition. Typical concentrations of the hydrogel forming polymer in the emulsion composition in accordance with the invention range from 0.1 to 5 weight percent, based on the total weight of the emulsion composition.

With regard to the aqueous phase or the water phase of the oil-in-water emulsion used in the emulsion composition no specific restrictions apply. Typically, water is the only solvent contained in the aqueous phase. The pH of the aqueous phase may be adjusted, where desired, to a pH in the range of 4 to 10, more preferably 6 to 8. No surfactants are needed in the aqueous phase, so that the aqueous phase is typically free of surfactants.

Suitable relative amounts of the dried hydrogel and the oil droplets in the dry composition in accordance with the second aspect of the invention can be selected in line with the above information, taking into account that the rehydration of the dry composition should be able to yield the emulsion composition in accordance with the invention.

In the dry composition in accordance with the invention comprising a mixture of the dried hydrogel and the oil droplets, the oil droplets are generally surrounded by the network structure of the polymer molecules forming the hydrogel. Upon rehydration, water infiltrates the network structure, so that an oil-in-water emulsion is formed which is entrapped in a hydrogel.

The emulsion composition in accordance with the first aspect of the invention may be conveniently prepared by a process which comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, and mixing the oil-in-water emulsion with a hydrogel, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil as defined above.

Suitable procedures will be known to the skilled person. For example, an emulsion can be prepared by weighing the oil including the hydrolyzable oil, adding the aqueous phase including, if desired, a buffer, and adding a suitable amount of the active agent. The active agent may be dissolved in an organic solvent in order to facilitate its mixing into the oil. The organic solvent, if used, can be removed at a later stage by methods established for the production of emulsions, e.g. by applying a vacuum. Alternatively, any optional solvent can be sonicated to facilitate the formation of oil droplets, and to partition the active agent in the oil droplets. Then, a hydrogel can be mixed with the oil-in-water-emulsion. Preferably, the mixing is accomplished with the hydrogel being in liquefied form e.g. at an increased temperature, so that the mixture can be allowed to gel by cooling.

The dry composition in accordance with the second aspect of the present invention is conveniently obtainable by removal of water from the emulsion composition in accordance with the first aspect of the present invention, preferably by freeze-drying the emulsion composition in accordance with the first aspect of the present invention. In other words, it can be prepared by a process which comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, mixing the oil-in-water emulsion with a hydrogel, and freeze-drying the obtained mixture, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil as defined above.

In order to stabilize the mixture of the hydrogel and the oil droplets during freeze drying, the emulsion composition can be surrounded by a suitable membrane, e.g. a cellulose membrane, which is stable during freeze-drying. Using such a membrane, water and optional solvent molecules can be removed from an emulsion entrapped by the hydrogel, while the hydrogel polymer and the oil of the oil droplets cannot permeate the membrane. In order to provide a pharmaceutical composition comprising the dry composition in accordance with the second aspect of the present invention, a pharmaceutical capsule can be used as such a membrane during the freeze-drying procedure. Thus, a capsule containing the dry composition can be directly obtained from the freeze-drying process.

Due to the removal of the aqueous phase from the oil-in-water composition during freeze drying, the oil droplets of the dry composition in accordance with the invention do not suffer from hydrolysis when the dry composition is stored. However, the dry composition can be rehydrated to reconstitute the emulsion composition by adding water to the dry composition. This rehydration can be accomplished prior to any application of the composition, e.g. prior to administrating the composition as a pharmaceutical composition to a patient. However, it is also possible to allow the rehydrating to take place in situ, e.g. in the body of a patient to which the dry composition has been administered.

Thus, to the extent that the active agent contained in the composition is a pharmaceutically active agent, both the emulsion composition in accordance with the first aspect of the invention and the dry composition in accordance with the second aspect of the invention is provided for use in medicine and for use in the treatment of the human or animal body by therapy or for prophylactic purposes. In particular, the compositions in accordance with the invention having a pharmaceutically active agent incorporated into the oil droplets (also referred to as pharmaceutical compositions in accordance with the invention) are suitable for use in the treatment or prevention of a medical condition to be treated or prevented by the controlled release of the pharmaceutically active agent.

For example, a pharmaceutical composition in accordance with the invention can be conveniently adapted for and used in the oral administration of the pharmaceutically active agent. One option as referred to above would be to include the composition into a pharmaceutical capsule. As another example, a pharmaceutical composition in accordance with the invention can be conveniently adapted for and used in the administration via subcutaneous injection.

Thus, the compositions in accordance with the present invention are also suitable for use in a method of treating or preventing a medical condition, said method comprising administering an effective amount of any such composition having a pharmaceutically active agent incorporated into the oil droplets, to a patient in need thereof. For example, as indicated above, the composition can be administered orally, e.g. when it is contained in a pharmaceutical capsule. As a further example, a method can be mentioned wherein the composition is administrated via subcutaneous injection. The following examples serve to further illustrate the invention.

Examples

Determination of water solubility

The solubility in water at a pH of 7.4 and a temperature of the water of 37°C of a hydrolyzable oil suitable as a component of the oil droplets in the compositions in accordance with the invention can be measured by mixing the hydrolyzable oil into an aqueous buffered solution at pH 7.4 (e.g. PBS buffer dissolved in water) and 37°C. The mixture is sonicated such that the tested oil is dispersed into oil droplets. The turbidity of the solution can be measured using a plate reader. The turbidity decays as the oil is hydrolyzing. At the point of time when all droplets have dissolved, i.e. when the turbidity of the test solution reaches that of a standard buffer solution, the concentration of the hydrolyzable oil is measured by HPLC. That concentration corresponds to the solubility of the hydrolyzable oil.

Determination of hydrolysis rate constants

The hydrolysis rate constants in water at a pH of 7.4 and a temperature of the water of 37°C of a hydrolyzable oil suitable as a component of the oil droplets in the compositions in accordance with the invention can be measured by completely dissolving the hydrolyzable oil into an aqueous buffered solution at pH 7.4 (e.g. PBS buffer dissolved in water) and 37°C. The evolution of the concentration of the hydrolyzable oil can be measured by HPLC. The concentration as a function of time is fitted with a 1^st order decay to measure the 1^st order reaction rate constant.

Preparation and testing of emulsion compositions

As hydrolyzable oils, acid anhydrides that phase separate into oil droplets when vigorously mixed with water were used. In the aqueous environment, the anhydrides hydrolyze into their corresponding carboxylates (cf. Fig. 1).

The carboxylic acid anhydrides used as hydrolysable oils in the examples include asymmetric ones, like 1, based on succinic anhydride derivatives with an unsaturated aliphatic tail, and symmetric ones, like 3, based on fatty acid anhydrides. Tests results are reported herein in particular for 2-decen-1-ylsuccinic anhydride (C10-SA, n=6 in 1, Fig. 1), 2- dodecen-1-ylsuccinic anhydride (C12-SA, n=8 in 1, Fig. 1) and 2-tetradecen-1-ylsuccinic anhydride (Cu-SA, n=10 in 1, Fig. 1) as well as hexanoic anhydride (C₆-A, m=4 in 3, Fig. 1), heptanoic anhydride (C₇-A, m=5 in 3, Fig. 1) and octanoic anhydride (C₈-A, m=6 in 3, Fig. 1).

As active agents, three hydrophobic drugs, Nimesulide, Nitrendipine, and Mebendazole with water solubilities below 1.0 mM were formulated in the tested emulsion compositions.

In order to formulate the active agents in an emulsion composition in accordance with the invention, first emulsions were prepared by weighing the anhydride (metastable oil) and adding 0.5 M 2-(A/-morpholino)ethanesulfonic acid (MES) buffer (pH 6.5) and 50 mM of the drug from a 5 mM stock solution in acetonitrile or ethanol. The acetonitrile or ethanol was removed from the formulation by a later freeze-drying step. The mixture was sonicated for 2 minutes to ensure the formation of anhydride droplets and to partition the drug in the anhydride. Then, a liquefied agar gel (at 90°C, 2% w/w stock in 0.5 M MES buffer pH 6.5) was added to the emulsion in a 1 :1 ratio. The resulting hydrogel-stabilized emulsion compositions thus contained 1% w/w agar gel at pH 6.5 with a drug concentration of 25 mM in the droplets. The emulsion composition was subsequently covered with buffer (0.5 M MES buffer, pH 6.5) to measure the release of the drug to the aqueous phase as schematically illustrated in Fig. 2.

In Fig. 3, representative traces of the cumulative drug release are shown. As a control, the release profiles of the two drugs (50 pM) in the absence of oil droplets from the 1% agar gel was measured. HPLC to measure the drug release from the hydrogel. As expected, it was found in these control measurements that the release followed first-order kinetics (initially fast, then slow) and the drug was released within 90 minutes (Fig. 3, triangles). In contrast, the use of the emulsion composition drastically delayed the drug release. The emulsion composition was made following the above-mentioned procedure, using 50 mM C₁₀-SA as metastable oil and 50 pM of the drug trapped in a 1% agar gel. Additionally, both release profiles showed a clear linear release of the drug over the entire release period (Fig. 3, squares). We found that after 20 hours, 50% of the drug was released, compared to the control experiments that implies that the presence of the oil droplets delays the release by a 30-fold. Furthermore, the release rates showed clear zero-order release, which means that the release was almost constant for the entire 20-hour period.

The emulsion compositions allow to release drugs with varying rates, but all of these rates are constant. For example, when the starting drug concentration is varied from 25 to 200 pM, all release profiles showed linear release, but with increasing release rate (Fig. 4). The result can be explained by considering that the emulsion in the emulsion composition has a lifetime that depends on the amount of the hydrolyzable oil. Loading the droplets with more drug will not affect that lifetime, but it will affect the amount of drug that is released over time.

Similarly, the effect of the amount of hydrolyzable oil dispersed into the emulsion composition on the drug release rate was tested. It was found that increasing the amount of hydolyzable oil increased the release period and decreased the release rate. With an increasing amount of metastable oil, the lifetime of the emulsion is increased. When the amount of initial drug concentration is fixed, but the lifetime increases, it naturally follows that the release rate decreases (Fig. 4).

With UV/Vis turbidity measurements, the lifetimes of the emulsions in the emulsion compositions could be determined, the approximate release period for different hydrolyzable oils could be assessed (Fig. 5). The used anhydrides in different concentration ranges cover lifetimes from 3 hours to 3.7 days. The results are also showing linear trends within the different measurement series, which support the concept of having a simple, versatile, and predictable system.

In order to test the emulsion compositions under conditions which specifically simulate those encountered in the human body in vivo, phosphate-buffered saline (PBS) with a pH value of 7.4 was used as a buffer for further experiments, and the temperature was raised to 37 °C. Moreover, the aqueous supernatant that covers the emulsion compositions was replenished consistently.

The zero-order release profile of the emulsion compositions could be maintained at least 8 hours using the in vivo simulating method, which underlines the robustness of the system for different temperatures, pH values, and internal fluxes. Furthermore, the tunability of release rates using varying concentrations of the hydrolyzable oil (Fig. 6a) and the drug (Fig. 6b) remained possible in the in vivo simulating setting. Several BCS class II drugs were tested (Fig. 6c). Nitrendipine, Nimesulide, Mebendazole, and Glyburide showed the desired zero- order release.

In order to provide a formulation which is storable, dry, stable, and easy to handle, the emulsion composition was subjected to freeze-drying (lyophilization). In order to stabilize the mixture of the hydrogel and the oil droplets during the freeze-drying process, the emulsion composition was transferred into a cellulose membrane that is stable during freeze-drying and not permeable for the hydrogel and the oil. Thus, a dry composition comprising a mixture of a dried hydrogel and oil droplets was obtained. In a pharmaceutical dosage form, the cellulose membrane can be replaced by a pharmaceutical capsule. Fig. 7 schematically illustrates the process including the freeze-drying step to provide the dry composition. During the freeze-drying step, organic solvent that is used for drug stock solutions is easily and entirely removed.

Rehydration of the system was performed simply by putting the membrane containing the powder of dry composition into a suitable container with PBS buffer at 37 °C. To best simulate an in vivo scenario, the buffer was exchanged periodically, and the release measured over time (Fig. 8). The release profile of the system is not significantly influenced by the freeze-drying within the first 10 hours and follows zero-order kinetics. The initial burst release remained unchanged that indicates that the hydrolysis could be avoided by freeze drying.

The content of the figures is summarized in the following:

Figure 1: Scheme of the used hydrolysable oils: asymmetric anhydride 1 with the corresponding di-carboxylate 2, symmetric anhydride 3 with corresponding carboxylate 4.

Figure 2: Schematic representation of the preparation of the emulsion compositions.

Figure 3: Representative traces of the cumulative drug release of 50 mM Nitrendipine (a) and Nimesulide (b) from the agar gel without the active emulsion (triangles) and with the active emulsion (squares). The active emulsion consists here of 50 mM C10-SA in 0.5 M MES buffer at pH 6.5 and 25 °C. The percentage of agar was 1.0% in 0.5 M MES buffer at pH 6.5.

Figure 4: Zero-order release rates of a) Nitrendipine and b) Nimesulide from an active emulgel with varying C10-SA and drug concentration. The concentration drug varied from 25 mM (triangles), 50 pM (squares), 75 pM (diamonds), 100 pM (triangles) to 200 pM (circles). The initial C10-SA varied from 7.5 mM to 100 mM.

Figure 5: Lifetimes of the emulsion in the emulsion compositions with different hydrolyzable oils measured by UV/Vis turbidity experiments at 500 nm.

Figure 6: a) Drug release rates of 50 pM Nimesulide and 50 pM Nitrendipine from an emulsion composition with varying C10-SA and C12_/14-SA concentrations, respectively; b) drug release rates of varying Nimesulide and Nitrendipine concentrations from Ci₀-droplets (150 mM) and Ci2m-droplets (50/40 mM), respectively; c) cumulative drug release from an emulsion composition containing C12 (10 mM). All experiments were carried out in 1% agar gel, PBS-buffer, pH 7.4, 37 °C. The error bar depicts the standard deviation from the average (n = 3). Figure 7: Additional steps to prepare storable dry compositions. Before freeze-drying, the emulsion composition was put into a cellulose membrane.

Figure 8: Cumulative drug release of 100 mM Nitrendipine from Ci4-droplets (100 mM) before (squares) and after (triangles) lyophilization of the emulsion composition.

Claims

1. A composition comprising

(i) a hydrogel, and

2. The composition in accordance with claim 1, wherein the hydrolyzable oil is a compound selected from an ester of a carboxylic acid, an amide of a carboxylic acid, an anhydride of a carboxylic acid, and combinations thereof.

3. The composition in accordance with claim 1 or 2, wherein the hydrolyzable oil is a compound of formula (I) or a compound of formula (II)

wherein, in formula (I),

R¹ is a hydrocarbon group having 3 to 18 carbon atoms,

R² is hydrogen or a hydrocarbon group having 3 to 18 carbon atoms, and the minimum total number of carbon atoms in R¹ and R² is 6, and the maximum total number of carbon atoms in R¹ and R²is 18; and wherein, in formula (II),

R³ is a hydrocarbon group having 4 to 11 carbon atoms, and

R⁴ is a hydrocarbon group having 4 to 11 carbon atoms.

4. A composition comprising

(i) a hydrogel, and

wherein, in formula (I),

R¹ is a hydrocarbon group having 3 to 18 carbon atoms,

R³ is a hydrocarbon group having 4 to 11 carbon atoms, and

R⁴ is a hydrocarbon group having 4 to 11 carbon atoms.

5. The composition in accordance with claim 3 or 4, wherein R¹ is C6-18 alkyl or C6-18 alkenyl, and R² is hydrogen.

6. The composition in accordance with any of claims 3 to 5, wherein R³ and R⁴ are independently C4-11 alkyl or C4-11 alkenyl.

7. The composition in accordance with any of claims 1 to 6, wherein the hydrolyzable oil accounts for 70 wt% or more of the total weight of the oil in the oil droplets as 100 wt%.

8. The composition in accordance with any of claims 1 to 7, wherein the active agent incorporated into the oil droplets is an active agent with a solubility in water at a pH of 7.4 and a temperature of the water of 37 °C of less than 1 mM.

9. The composition in accordance with any of claims 1 to 8, which is a pharmaceutical composition having a pharmaceutically active agent incorporated into the oil droplets.

10. The composition in accordance with any of claims 1 to 9, wherein the hydrogel is a non-charged hydrogel.

11. The composition in accordance with any of claims 1 to 10, wherein the hydrogel is selected from an agar gel, a glycogen gel and a cellulose gel.

12. A composition which is obtainable by removing water from the composition in accordance with any of claims 1 to 11.

13. A composition comprising a mixture of

(i) a dried hydrogel, and

(ii) oil droplets, wherein an active agent is incorporated into the oil droplets, and wherein the oil droplets comprise a hydrolyzable oil as defined in claims 1 to 11.

14. A process for the preparation of a composition in accordance with any of claims 1 to 11 , which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, and mixing the oil-in-water emulsion with a hydrogel, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil as defined in any of claims 1 to 11.

15. A process for the preparation of a composition in accordance with claim 12 or 13, which process comprises the steps of providing an oil-in-water emulsion, with an active agent being incorporated in the oil droplets dispersed in the oil-in-water emulsion, mixing the oil-in-water emulsion with a hydrogel, and freeze-drying the obtained mixture, wherein the oil droplets dispersed in the oil-in-water emulsion comprise a hydrolyzable oil as defined in any of claims 1 to 11.

16. The process of claim 15, wherein the mixture of the hydrogel and the oil-in-water emulsion is surrounded by a membrane during freeze-drying.