CONTROLLED RELEASE FROM PARTICLES ENCAPSULATED BY MOLECULAR LAYER DEPOSITION

Abstract

The invention provides a slow-release material comprising particles, wherein the particles comprise a core comprising an active component and a multilayer shell, wherein the multi-layer shell comprises a molecular layer deposition (MLD) multi-layer, wherein the active component comprises one or more of a pharmaceutical compound and a nutraceutical compound, for use in the treatment of a disease.

Claims

1.-22. (canceled)

23. A slow-release material (1) comprising particles (100), wherein the particles (100) comprise a core (110) comprising an active component (10) and a multi-layer shell (120), wherein the multi-layer shell (120) comprises a molecular layer deposition (MLD) multi-layer (1200), wherein the active component comprises one or more of a pharmaceutical compound and a nutraceutical compound, for use in the treatment of a disease, and wherein each layer (121) of the multi-layer shell (120) comprises a group defined by formula (I): ##STR00009## wherein R1, R2, R3, and R4 are independently selected from the group consisting of a carbon comprising group, wherein Z1 and Z2 are each independently selected from an oxygen or nitrogen comprising group, and wherein R2 is optionally present.

24. The slow-release material (1) according to claim 23, wherein the core (110) comprises a diameter (d1) selected from the range of 1 nm-2 mm, and wherein the multi-layer shell (120) comprises in the range of 2-1000 layers (121).

25. The slow-release material (1) according to claim 23, wherein a first molecular layer (121a) is covalently linked to a surface (111) of the core (110).

26. The slow-release material (1) according to claim 25, wherein R1=R3=C, R2=CH.sub.2, R4=-(CH.sub.2)C(CH.sub.2CH.sub.3)—, and Z1=Z2=O.

27. The slow-release material (1) according to claim 23, wherein the active component (10) comprises a pharmaceutical compound, and wherein the core further comprises a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable filler.

28. The slow-release material (1) according to claim 23, wherein the active component (10) comprised by said core (110) has an active component solubility in water, wherein the multi-layer shell (120) has a multi-layer shell solubility in water, wherein the multi-layer shell solubility is smaller than the active component solubility.

29. A method for the production of a slow-release material (1) according to claim 23, the method comprising: fluidizing particles (100) comprising an active component (10) in a reactor (1000), wherein the active component comprises one or more of a pharmaceutical compound and a nutraceutical compound; applying molecular multi-layer deposition with self-terminating reactions on said fluidized particles (100) in said reactor (1000), wherein sequentially compounds (II) and (III) are reacted: ##STR00010## wherein R1, R2, R3, and R4 are independently selected from the group consisting of a carbon comprising group, wherein R2 is optionally present, wherein A1 and A2 are independently selected from OH, Cl, and —OR5, wherein R5 is selected from the group consisting of a carbon comprising group and a silicon comprising group, wherein Z11 and Z12 are each independently selected from an OH comprising group, an NH comprising group and an NH.sub.2 comprising group; removing the thus obtained particles from said reactor (1000), to provide said slow-release material (1).

30. The method according to claim 29, wherein during the molecular multi-layer deposition the reactor (1000) is subjected to a vibration having a frequency selected from the range of 1-200 Hz.

31. The method according to claim 29, wherein the reactor has a top part (1076), wherein the method further includes providing a counter flow (1020) from the top part (1076) into the reactor (1000).

32. The method according to claim 31, wherein the counter flow (1020) is provided into the reactor (1000) via a micro jet (1004).

33. The method according to claim 29, wherein the molecular multi-layer deposition is executed at a temperature selected from the range of 35-150° C. and at a pressure selected from the range of 0.8-2 bar.

34. The method according to claim 29, wherein the particles (100) comprise a surface (111) comprising amine groups.

35. The method according to claim 29, wherein a number of times sequentially three compounds are reacted, and wherein the thus obtained molecular layer deposition (MLD) multi-layer (1200) comprises a stack of layers (121) with each layer (121) comprising the reaction product of the three compounds.

36. The method according to claim 29, wherein one or more of the self-terminating reactions comprise a ring opening reaction.

37. The method according to claim 29, wherein compound (II) is selected from an oligo carboxylic acid and an oligo acid chloride analogue, and wherein compound (III) is selected from a polyol and a polyamine.

38. The method according to claim 29, wherein the core (110) comprises a diameter (d1) selected from the range of 1 nm-2 mm, and wherein the method comprises applying molecular multi-layer deposition until a multi-layer shell (120) of 2-100 layers (121) is obtained.

39. The method according to claim 29, further comprising one or more of providing an additional coating, producing a dosage form comprising the slow-release material (1), and packaging the slow-release material (1) or dosage form, respectively.

40. A reactor (1000) for fluidizing particles (110) comprising a diameter (d1) selected from the range of 1 nm-2 mm, wherein the reactor (1000) comprises a first inlet (1001) for introduction of one or more reactants in the gas phase, wherein the reactor (1000) further comprises a vibration generator (1600) configured to subject the reactor (1000) to a vibration having a frequency selected from the range of 1-200 Hz, wherein the reactor (1000) further comprises a second inlet (1002) for a gas, configured to provide during operation a counter flow relative to a flow introduced in the reactor (1000) via the first inlet (1001).

41. The method according to claim 29, wherein the method comprises depositing a molecular layer deposition (MLD) multi-layer (1200) onto particles being pneumatically transported in a tube, said process comprising: (i) providing a tube having an inlet opening and an outlet opening; (ii) feeding a carrier gas entraining particles into the tube at or near the inlet opening of the tube to create a particle flow through the tube; (iii) injecting a first reactant into the tube via an injection point downstream from the inlet opening of the tube for deposition on the surface of the particles in the particle flow in a self-terminating reaction; and (iv) injecting a second reactant into the tube via a further injection point downstream from the injection point of the first reactant for deposition on the surface of the particles in the particle flow in a self-terminating reaction.

42. A core-shell particle (100), comprising a core (110) comprising an active component (10) and a shell (120), wherein the shell (120) comprises a plurality of polymers, with each polymer attached with one end to the core, and each polymer comprises a plurality of groups defined by formula (I): ##STR00011## wherein R1, R2, R3, and R4 are independently selected from the group consisting of a carbon comprising group, wherein Z1 and Z2 are each independently selected from an oxygen or nitrogen comprising group, and wherein R2 is optionally present.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding reference symbols indicate corresponding parts, and in which:

[0076] FIGS. 1a-1d provide illustrations of the reactions involved in an MLD process;

[0077] FIG. 2 provides a schematic diagram of the experimental setup used for the MLD process;

[0078] FIG. 3 provides FTIR spectra (absorption (A) vs. wavenumber (in cm.sup.−1)) for 2, 6 and 10 cycles sample;

[0079] FIG. 4 provides an UV-vis absorbance (AS) versus time (seconds) test result for protein particles coated with different numbers of cycles; and

[0080] FIGS. 5a-5b schematically depict some aspects of the invention.

[0081] The schematic drawings are not necessarily on scale.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0082] To demonstrate the concept, we used protein particles as the substrate and the precursors used are malonyl chloride and 1,2-butanediol. An illustration of the reactions involved is shown in FIG. 1a. References RE1-RE3 refer to reactions 1-3. Note that reaction 3 is the same as reaction 1, hence, with reaction 3 and (further reaction analogous to reaction two) a second layer may be formed. Reference 100 indicates a particle and reference 110 indicates a core. The particle, yet without multi-layer layer, i.e. in fact the core 110, has a surface 111. Reference 121 indicates a layer (which is formed by the two self-terminating reactions; reference 121a indicates the first layer, which is covalently linked to the surface 111. The basic compound formed, here an ester, is indicated with reference (I). By way of example, amine groups are shown at the surface 111 of the bare particle 100. As can further also be seen in FIG. 1b, the two self-terminating reactions include a first reactant and a second reactant (embodiments thereof are herein also indicated as compounds (II) and (III), which after the two self-terminating reactions lead to a monolayer 121. The parts of the monolayer originating to these two reactants are in FIG. 1a indicated as A and B. RE1 and RE3 may thus essentially be the same reactions.

[0083] More in general, the elementary reactions that can be involved are indicated in FIG. 1b. The amine group on the surface of the protein particles acts as the active group for reaction with the acyl chloride group of malonyl chloride during the first reaction step. In the second reaction step, the unreacted acyl chloride group of malonyl chloride which is now attached to the surface of the substrate acts as the active site for the reaction with the hydroxyl group of 1,2-butanediol. In the third reaction step, the unreacted hydroxyl group of 1,2-butanediol reacts with the acyl chloride group of malonyl chloride.

[0084] FIG. 1b schematically depicted the two compounds II and III which may result in chains including group I after a reaction of compounds II and III. In these formulas, R2 may be available. However, R2 is not necessarily available. This is indicated in FIG. 1c. When R2 is not available, the formulas as indicated in FIG. 1d may be applied.

[0085] Only the first coating cycle involves reaction step one and two, while subsequent coating cycles involves reaction step three and two. Each cycle generates a single layer. Note that the numbering is only used to differentiate between reactions. Hence, step three and two may herein also be indicated as a first self-terminating reaction and a second self-terminating reaction.

[0086] In an experiment, 2 g of protein particles with an average diameter of 200 μm is suspended in an upward gas flow of pure N.sub.2, this is called a fluidized bed. N.sub.2 acts as the carrier gas for feeding the precursors into the fluidized bed reactor (FBR). A schematic diagram of the experimental setup is shown in FIG. 2. The reactor or fluidized bed reactor is indicated with reference 1000.

[0087] The FBR primarily consists of a vertical glass tube with an inner diameter of 2.6 cm and length of 40 cm with thermocouples inserted at the entrance and exit. The FBR is maintained at a temperature between 40° C. and 45° C. using an infrared lamp. It may be desired to maintain considerably low temperatures because the protein used is found to denature at a temperature above 55° C. The denaturation temperature of the protein to a great extent limited the choice of precursors for the MLD process. Due to the low vapor pressures of malonyl chloride and 1,2-butanediol, respectively, at room temperature they are preheated to 40° C. and 115° C. in bubblers 1077,1078, respectively. A distributor plate 1079 is provided at the entrance or inlet 1001 of the FBR to ensure uniform distribution of the inlet gas stream mixture. By measuring the particle bed height variation with flow rate, the minimum velocity required to keep the particles afloat in N.sub.2 gas is determined to be 2.7×10.sup.2 ms.sup.−1. This velocity is often referred to as the minimum fluidization velocity. The unreacted precursor and by-product of the reaction HCl is trapped using a mineral oil cold trap 1075 at the exit or outlet 1003 of the FBR. We employ two methods to improve the fluidization of the particles: mechanical vibration of the FBR at a frequency of 50 Hz, and a microjet 1004 of 100 μm. The microjet is inserted into the FBR from the top and the mechanical vibrator is fixed at the bottom of it. The microjet ensures good fluidization by breaking the agglomerates formed during the coating process. Reference 1700 indicates the microjet unit, further comprising a gas flow generator 1073, with gas 1074, such as N.sub.2. Reference 1002 indicates the outlet or nozzle of the microjet 1004. Reference 1600 indicates the vibration generator. References 1072 indicate valves. References 1071 indicate a heating system. Reference 1076 indicates an expansion of the column diameter to reduce the outflow of particles. Reference 2 indicates an MLD apparatus, comprising the reactor 1000 and further elements, including optional items such as the microjet unit 1700 and the vibration generator 1600, to execute the method as defined herein. Here, by way of example the gas flow generator 1073 is used for the microjet unit 1700 and the gas flow for generating the fluidized bed. Of course, this can be two or more (independent) gas flow generators.

[0088] Particles coated to different number of cycles are prepared. A typical coating cycle consists of four steps: 30 s dosage of malonyl chloride; minimum 2 min of purging with pure N.sub.2 to remove the unreacted precursor; 30 s dosage of 1,2-butanediol and finally purging with pure N.sub.2 for at least 2 min. We observed a tendency for particle agglomeration during the reaction steps in a coating cycle which aggravates with increase in number of cycles. This increased agglomeration affects the fluidization of the particles and in certain cases the fluidization is completely lost. Purging the FBR with high flow rate N.sub.2 gas for long duration of time reinforced fluidization. Hence, for later cycles the reactor was purged until the fluidization was completely re-established. Particles were coated with 2, 6 and 10 MLD cycles. In this embodiment, by way of example three gas transport lines 1073a-1073c are depicted, for providing gas to provide a fluidized bad (gas transport line 1073a), to provide a first reactant (gas transport line 1073b), and to provide a second reactant (gas transport line 1073c). Reference 1019 indicates the direction of the gas flow in the fluidized bed reactor. The microjet unit 1700 may provide a counter flow 1020.

[0089] Fourier transform infrared (FTIR) spectroscopy has been used to characterize the coating of protein particles. FTIR spectra are obtained using a Nicolet 8700 FTIR spectrometer (Thermo Electron Corporation) operating with a liquid N.sub.2 cooled KBr/DLaTGS D301 detector. FTIR spectra of the coated protein particles are obtained by pressing the sample onto KBr salts and the data is collected with a resolution of 4 cm.sup.−1 averaged over 128 scans. The FTIR spectra of the coated particles shown in FIG. 3 are subtracted results from the spectra of the uncoated particle.

[0090] In FIG. 3, three distinct peaks are observed very close to 1480 cm.sup.−1, 1736 cm.sup.−1 and 2971 cm.sup.−1, these correspond respectively to the stretching of [—CH.sub.2—],[—COO—] and [CH.sub.3—] groups. Increase in the absorbance peak due to [—COO—] and [CH.sub.3—] stretching indicates the increase in coating thickness with number of cycles. In FIG. 3, the x-axis indicates the wavenumber in cm.sup.−1, and the y-axis indicates the absorbance (in arbitrary units). References 2C, 6C, and 10C indicates the number of cycles, being respectively 2, 6, and 10.

[0091] Dissolution experiments have been performed to study the controlled release of the coated protein samples. All the dissolution experiments have been performed at room temperature and atmospheric pressure. 0.15 g of a coated particle sample is dissolved in 150 ml of deionized water. The resulting mixture was stirred with a magnetic stirrer to ensure uniform dispersion of the particles in deionized water. However, due to their low density most of the coated particles remain on the surface of the solution. Samples have been collected at regular intervals for a time period of 30 min. The collected samples are immediately filtered through a 0.45 μm pore size polyvinylidene difluoride membrane (MillexOR) to avoid further dissolution of protein particles. After a time period of 30 min, undissolved protein particles denatured to form strands in the solution.

[0092] UV-vis spectroscopic measurements (UV-1800, Shimadzu) were performed on the collected dissolution experiment samples of uncoated and coated protein particles at a wavelength of 260 nm. The results are shown in FIG. 4.

[0093] In FIG. 4, AS indicates the scaled absorbance is defined as (A(t)−A(t=0))/(A(t=1800 s)−A(t=0)), where A(t) is the absorbance at time t and A(t=0) is assumed to be zero. Here, scaled absorbance gives a measure of scaled concentration because absorbance scales linearly with concentration. The solution containing uncoated sample attains maximum concentration in about 10 s, while the coated samples dissolve at a much slower rate. In the inset of FIG. 4, the UV-vis test results are plotted on a log-log scale. Two distinct regions are observed: initial short time scale ˜ 30 s corresponding to a fast release of the coated protein and the long time scale ˜ 1000 s corresponding to a slow release of the coated protein. References 0C, 2C, 6C, and 10C indicates the number of cycles, being respectively 0, 2, 6, and 10. The x-axis indicates the time (in seconds).

[0094] The fast and slow regions are fitted individually to a power law function which scales with time as t.sup.α. The values of α.sub.fast for 2, 6 and 10 cycles sample, are respectively 0.482±0.166, 0.425±0.121 and 0.422±0.059. α.sub.fast values obtained are close to 0.5 which is observed in diffusion governed dissolution mechanism models. We suspect the close resemblance of the fast release exponent to that of diffusion governed drug release mechanism models could be due to the presence of protein particles whose surface area is not completely coated. These particles are formed as a result of continuous breakage and formation of agglomerates, respectively, during purging and precursor dosage periods. For the 2 cycles sample, α.sub.slow ≈ 0 indicating that the maximum concentration has been attained after a time period of 100 s. However, for 6 and 10 cycles sample, respectively, α.sub.slow is found to be 0.058±0.008 and 0.117±0.013.

[0095] In conclusion, we found that with increase in coating cycles of MLD the thickness of coating increases as shown by FTIR. We also demonstrate experimentally that controlled release of protein particles can be realized by MLD. The controlled-release behavior is validated through dissolution experiment of coated particles wherein the decrease in the rate of dissolution is observed with increase in the number of coating cycles.

[0096] This proof-of-principle demonstrates that MLD of fluidized particles is an attractive way to give protein materials tunable controlled-release properties.

[0097] FIG. 5a schematically shows the (particulate) slow-release material 1, here by way of example only schematically indicated with a single particle 100, wherein the particle 100 comprise a core 110 comprising an active component 10 and a multi-layer shell 120. The multi-layer shell 120 comprises a molecular layer deposition MLD multi-layer 1200. As indicated above, especially the active component comprises one or more of a pharmaceutical compound and a nutraceutical compound, such as for use in the treatment of a disease. The core 110 comprises a diameter d1, such as selected from the range of 1 nm-2 mm. The multi-layer shell 120, especially the molecular layer deposition multi-layer 1200 comprises a layer thickness d2 selected from the range of 2-1000 layers 121. The layers are herein indicated with references 121a, 121b, etc.

[0098] Small polymer chains (oligomers when there are two layers) are in this way grown to the surface of the core 10. This may lead to a kind of spaghetti configuration of polymers to the surface, with units I available in one or more, or substantially all chains. Step by step these chains are formed in a molecular layer deposition process leading to layer formation, which layers are provided by the groups I. This is schematically shown in FIG. 5b. Therefore, in embodiments the invention provides core-shell particles, wherein the shell is provided by a plurality of polymer chains, each (chemically) attached with one end to core, and each polymer comprising a one or more, especially a plurality, of groups I.

[0099] A further MLD coating was formed by exposing dried powders (containing an active ingredient) alternatively to diethyl succinate and 1,4-butanediol. The precursors were contained in 100 mL glass round bottom flasks heated at respectively 80-95° C. and 100-125° C. by heating mantles. Precursors were transported in a nitrogen flow (0.4 L/min). The tube lines heading to the column were heated by heating tapes to prevent precursor condensation. Presence of MLD coating was confirmed by delayed release of active ingredient.

[0100] The term “substantially” herein, such as in “substantially consists”, will be understood by the person skilled in the art. The term “substantially” may also include embodiments with “entirely”, “completely”, “all”, etc. Hence, in embodiments the adjective substantially may also be removed. Where applicable, the term “substantially” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. The term “comprise” includes also embodiments wherein the term “comprises” means “consists of”. The term “and/or” especially relates to one or more of the items mentioned before and after “and/or”. For instance, a phrase “item 1 and/or item 2” and similar phrases may relate to one or more of item 1 and item 2. The term “comprising” may in an embodiment refer to “consisting of” but may in another embodiment also refer to “containing at least the defined species and optionally one or more other species”.

[0101] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0102] The devices herein are amongst others described during operation. As will be clear to the person skilled in the art, the invention is not limited to methods of operation or devices in operation.

[0103] It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. Use of the verb “to comprise” and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. The article “a” or “an” preceding an element does not exclude the presence of a plurality of such elements. The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In the device claim enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0104] The invention further applies to a device comprising one or more of the characterizing features described in the description and/or shown in the attached drawings. The invention further pertains to a method or process comprising one or more of the characterizing features described in the description and/or shown in the attached drawings.

[0105] The various aspects discussed in this patent can be combined in order to provide additional advantages. Further, the person skilled in the art will understand that embodiments can be combined, and that also more than two embodiments can be combined. Furthermore, some of the features can form the basis for one or more divisional applications.