EP4188335A2

EP4188335A2 - Pharmaceutical microsphere compositions and methods

Info

Publication number: EP4188335A2
Application number: EP21763236.3A
Authority: EP
Inventors: Ian LANGER; Ronald E. Betts; Beatris Flores
Original assignee: Biotronik AG
Current assignee: Biotronik AG
Priority date: 2020-07-29
Filing date: 2021-07-28
Publication date: 2023-06-07
Also published as: WO2022023414A3; WO2022023414A2

Abstract

This application relates generally to the field of materials and manufacturing methods involving microsphere compositions and pharmaceutical applications related thereto.

Description

PHARMACEUTICAL MICROSPHERE COMPOSITIONS AND METHODS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Drug microspheres are attracting considerable interest and development activity. This is a result of the understanding of numerous potential advantages over traditional drug forms and delivery methods. Some advantages include the tailoring and extending of drug release rates, increased drug bioavailability, protection of labile drugs, targeting drugs to a specific site, and production of novel drug product forms for improved patient comfort and compliance.

Two broad drug microsphere classifications that have been defined in the art include, on the one hand, those containing polymers and, on the other hand, those that do not. As polymer incorporation can be required or aid in certain performance properties of traditional drug microspheres, there is a large body of published literature on this area. A recent review of this subject is incorporated for easy reference (Crucho, et al., Mater Sci Eng C , 80:771-784, 2017).

Typically, a drug is dissolved in a polymeric carrier solution, then particles are fabricated by coacervation with a second liquid phase followed by solvent removal. This results in particles containing the active drug dispersed in an amorphous polymer particle. A second method to prepare polymer-containing microspheres utilizes spray drying wherein the active drug is dispersed in the solubilized polymer carrier solution, then atomized into hot gas to evaporate the solvent. Most methods of preparing polymer-containing microspheres are complicated, requiring several steps, along with producing low yield. Such known methods can also utilize water immiscible solvents such as chloroform and surfactants that can promote degradation of labile drugs and are difficult to remove from the final product. Additional drawbacks to existing solutions in the field include the use of complicated production machinery in order to process polymeric solutions.

Drug microspheres that do not contain polymers have received less attention. A possible method to prepare these materials is by the use of spray drying. This method frequently utilizes large solvent volumes and requires costly equipment and facilities. A report on pharmaceutical spray drying is incorporated by reference (Arpagaus, Int J Med Nano Res, 5.026, (5)1, 2018) and provides background in the relevant art.

There is a need in the state of the art to improve upon the above described, known deficiencies in the scalable production of microsphere compositions by utilizing distinct, improved and novel processing elements, along with less toxic materials included in the production. There is also a need to improve upon the equipment required to produce such compositions in order to reduce production costs without sacrificing drug purity or yield.

SUMMARY OF THE INVENTION

The present invention provides for a method of forming a microspherical hydrophobic material onto at least one substrate, comprising: (a) providing a drug composition; (b) solubilizing the drug composition in at least one solvent; and (c) applying the resultant mixture of step (b) directly to a surface of the at least one substrate. Formation of the microspherical hydrophobic material is observed upon evaporation of the at least one solvent. With advantage the process as outlined above provided access to the formation of microspherical hydrophobic material without the need of forming droplet or vaporizing the solvent/drug solution or coacervation and the like. The microspherical hydrophobic material can be formed directly on a desired substrate without any intermediate steps or additional steps for forming the microspherical hydrophobic material prior to adhering the material to the substrate. Preferably, the drug is a macrocyclic triene immunosuppressive compound selected from the group consisting of rapamycin (sirolimus), everolimus, zotarolimus, biolimus, novolimus, myolimus, temsirolimus and rapamycin derivatives, such as compounds having the structure of rapamycin but with a substituent at the carbon corresponding to the 42 or 40 carbon. Optionally, the at least one substrate is selected from the group consisting of inorganic substrates, organic substrates and biological substrates. More preferably, the at least one substrate is a planar substrate. Preferably, the forming of the microspherical hydrophobic material occurs during an evaporation stage of the at least one solvent from the surface of the at least one planar substrate. Thereby, the evaporation occurs from the surface of the substrate, contrary to an evaporation in the air and an adhering of such particle to the surface. Preferably, the solvent is a dry solvent. A dry solvent is to be understood that measures have been applied to remove water from it. The extent of the removal can usually range from a simple distillation of the solvent to treating and storing the solvent after or during distillation with a drying agent such as sodium, potassium, NaAlH4 and the like. Preferably, the solvent contains less than 7% water, more preferably less than 3% water, even more preferably less than 1% water and most preferably less than 0.01% water. Suitable solvent are organic solvents such as alcohols, in particular, C1 to C3 aliphatic alcohols, acetone, ethers, in particular diethyl ether, chloroform, dichloromethane, acetonitrile, hexane and pentane. Particularly preferred are C1 to C3 alcohols, for instance methanol or ethanol.

Preferably, the solvent is a C1 to C3 alcohol. More preferably, the drug is CRC-015. Optionally, one or more additional drugs are included with the solubilizing of the drug in a least one solvent. Preferably, the drug composition is solubilized in at least one solvent in the absence of an excipient. Alternatively, the at least one substrate is made of a mixed composition. Also, it is preferred that the step of evaporating the of the at least one solvent occurs without means for accelerating evaporation, for example by slight wind, stream of air. If evaporation occurs slowly a narrow particle size distribution is observed. In case strong means for accelerating evaporation is applied like a stronger gas stream, heating the solvent close or above the boiling temperature of the at least one solvent formation of microspherical hydrophobic material is not observed. In terms of a gas stream it is preferred if gas is moving over the surface of the solution slower than 0.2 m/s. The concentration of the drug composition in the at least one solvent is supposed to be in a range of 0.1 to 200 mg/ml. In a preferred embodiment the concentration is in the range of 10 to 100 mg/ml. In the aforementioned range a narrow particle size distribution is observed. Also, in case of a higher drug concentration as defined above better adhesion of the microspherical hydrophobic material on the substrate could be observed. In another aspect, the present invention includes a composition comprising at least one microspherical hydrophobic material formed by in situ deposition of the hydrophobic material in the absence of an excipient applied directly to a surface of at least one substrate. In one preferred embodiment the at least one microspherical hydrophobic material formed the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, has the following structure: where R is C(O)-(CH₂)n-X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3-8 carbons and optionally contains one or more unsaturated bonds. In a most preferred embodiment, C(O)-(CH₂)n- X has one of the following structures:

In one embodiment the microspherical hydrophobic material consists of the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above. In another embodiment the microspherical hydrophobic material comprises the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above. One particularly preferred embodiment includes microspherical hydrophobic material being formed from the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above and shellac. The ratio between the two compounds varies from 5: 95 by weight to 95:5 by weight. In a preferred embodiment the microspherical hydrophobic material has a content of shellac being higher than 50% by weight. Microspherical hydrophobic material comprising shellac and the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above has the advantage of providing the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above to the intestinal system by oral administration. Shellac is capable of withstanding highly acidic environments of the stomach but tends to dissolve at a relatively higher pH such as those in the intestine or colon, thus protecting the drug from stomach dissolution, degradation and metabolism and delivering the drug in a more concentrated form for gut uptake.

One further embodiment includes microspherical hydrophobic material being formed from the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, as defined above and alisertib. The ratio between the two compounds varies from 5: 95 by weight to 95:5 by weight. In a preferred embodiment the microspherical hydrophobic material has a content of alisertib being less than 50% by weight.

A further preferred embodiment is directed to microspherical hydrophobic material, paclitaxel as well as paclitaxel with the inclusion of rapamycin or derivative thereof as defined herein and paclitaxel. In a specific embodiment the microspherical hydrophobic material consist of paclitaxel and the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, has the following structure: where R is C(0)-(CH₂)_n-X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3-8 carbons and optionally contains one or more unsaturated bonds. In a most preferred embodiment, C(0)-(CH₂)_n- X has one of the following structures:

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosed subject matter contained herein is best described in conjunction with the accompanying drawings, in which: Figure 1 shows a representative illustration of one of the preferred embodiments of depositing the dissolved solvent-drug mixture onto a substrate.

Figure 2 shows SEM images of different examples of drug spheres formed on glass substrate produced from various API drugs dissolved in methanol at approximately 2 mg/ml. Figure 3 shows SEM images of drug spheres formed on glass substrate with alternative solvents ethanol and acetone.

Figure 4 shows SEM images of drug microspheres formed on alternative substrates for use in evaluating drug microsphere formation.

Figure 5 shows a SEM image of a multi drug microsphere containing CRC-015 and alisertib on glass substrate.

Figure 6 shows SEM images of shellac flake as a substrate for use in the embodiments described in the present invention. (A) shellac only in methanol; (B) shellac + CRC015 in methanol on glass substrate; and (C) CRC-015 in methanol deposited on shellac flake.

Figure 7 shows SEM images of drug microspheres attached to shellac particles during simulated in vivo gastric conditions. (A) after 15 minutes; (B) after 30 minutes; (C) after 45 minutes; and (D) after 60 minutes of shaking.

Figures 8 -12 show SEM images of drug microspheres attached to tissue substrates.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term “macrocyclic triene immunosuppressive compound” includes rapamycin (sirolimus), everolimus, zotarolimus, biolimus, novolimus, myolimus, temsirolimus and the rapamycin derivatives described in this disclosure.

As used herein, the term “microsphere” or “microspherical” includes small, largely spherical particles with diameters in the nanometer to micrometer range. The present invention provides for materials and methods for the novel production of drug microspheres for use in treating certain diseases or conditions.

Certain advantages of the preferred embodiments of the present invention include, but are not limited to, increasing drug yield (even when using lipophilic drug compounds) on the milligram scale or larger, reducing the complexities associated with microsphere formation (including reduction of staff training and expensive equipment requirements), dramatically reducing processing time (resulting in diminishing likelihood of drug breakdown and lowering procedure expenses) and removing expensive materials (such as volatile compounds and costly synthetic polymers) from the productions steps.

The present invention relates to methods and processing steps that provide for the formation of drug microspheres after solubilizing at least one drug compositions (or multiple drug compositions) in various solvents. This solubilizing or dissolving step is followed by dispensing the resulting mixture onto a substrate. FIG. 1 illustrates one embodiment of how the mixture is dispensed onto a particular substrate. Preferably, a syringe is utilized to dispense the dissolved drug mixture onto a substrate. Alternatively, a pipette may be used in a similar fashion.

After depositing the solvent-drug mixture onto the substrate, evaporation of the mixture results in formation of drug microspheres on the substrate surface. Optimization of production conditions may result in specific improvements to the final product, for example, control of sphere size or automation of the processing steps.

Preferably, the drug as used in the present invention is a macrocyclic triene immunosuppressive compound selected from the group consisting of rapamycin (sirolimus), everolimus, zotarolimus, biolimus, novolimus, myolimus, temsirolimus and rapamycin derivatives, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates. More preferably, the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, has the following structure:

where R is C(O)-(CH₂)n-X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3-8 carbons and optionally contains one or more unsaturated bonds. In a most preferred embodiment, C(O)- (CH)n-X has one of the following structures: Examples

Example Drug Formulations:

The macrocyclic triene immunosuppressive compound of the present invention has more than one embodiment and may be described as comprising at least one of the following species from Table 1:

Table 1

Description of CRC-015 species

CRC-015, as referred to herein, is a term meant to encompass a genus and used to refer to each of the following species from Table 1: CRC-015a, CRC-015b, CRC-015c, CRC-015d, CRC- 015e, CRC-015f, CRC-015g, and CRC-015h.

I. Imaging of drug microspheres formed on substrate

Various drugs were dissolved in methanol at approximately 2 mg/ml, with the resulting mixture deposited on a glass substrate. SEM images of the resulting drug spheres are shown at FIG. 2. As evidenced by the images, drug sphere size, shape and volume differs depending on drug characteristics after dissolved in alcohol solvent and evaporated onto glass substrate in accordance with the methods described in the present invention.

FIG. 3 shows drug spheres formed using alternative solvents to the methanol utilized in

FIG. 2.

II. Formation of drug microspheres formed in various substrates

Various substrates other than glass were evaluated to assess microsphere quality and characteristics after deposition and evaporation of drug mixtures. The results of the evaluation of various substrates is quantified through SEM images and can be found at FIG. 4.

III. Formation and evaluation of multi drug microspheres

Multidrug microspheres can also be formed when two or more drugs are dissolved in the same solution. C1inical relevance for this discovery is evidenced by the recent report that combination therapy of alisertib and everolimus resulted in improved cancer inhibition ( Chem Eng News, July 2, 2018, p.3).

In the present example, equal parts of 2 mg/ml solutions of CRC-015 and alisertib in methanol were combined and dispensed on glass. The utility of this is both drugs could be delivered simultaneously in the same form, at the same time and same site from one formulation. FIG. 5 shows SEM imaging of the resulting CRC-015 + alisertib drug microspheres on glass substrate.

IV. Evaluation of shellac as an alternative substrate

Shellac is a natural material that is largely water insoluble at low pH conditions but will dissolve at a relatively higher pH. For this reason, shellac has been used by the pharmaceutical industry for decades as an enteric coating. This coating is a polymer barrier on oral medication that prevents or reduces dissolution or disintegration of the drug in the low pH of the gastric environment. Reduced drug dissolution in the stomach allows passage of the drug to intestine or colon, where a higher pH results in drug release. This property frequently results in enhanced drug bioavailability and/or for targeted drug delivery to that GI region ( World J Gastroenterol. 2014 Apr 21; 20(15): 4178-4188).

Surprisingly, it was found that drug microspheres can be formed directly on shellac surfaces. It was also discovered that shellac, by itself and in combination with drug API materials, will form shellac + drug microspheres on other substrates. Fig. 6 shows various SEM images of shellac microspheres: (A) dissolved only in methanol; (B) shellac + drug (CRC-015) microspheres in methanol on glass substrate; and (C) drug (CRC-015) microspheres in methanol deposited on shellac flake.

V. Evaluation of drug microspheres attached to shellac particles under gastric conditions An experiment to further investigate properties of drug microspheres deposited onto shellac flakes was conducted. CRC-015 (80 mg/ml) was dissolved in methanol and 1-6 pi solution was deposited to both top and bottom of shellac surfaces with drying of each to allow for drug microsphere formation.

The resulting drug/shellac particles were placed into 30 ml simulated gastric fluid (pH 1.0- 1.4) contained in 30 ml glass vials maintained at 37°C and allowed to horizontally reciprocate at 40 cycles per minute. The resulting particles were removed from separate vials at 15, 30, 45 and 60 minutes, allowed to air dry and examined by SEM.

It was discovered that drug spheres were still maintained on the shellac particles of this novel oral dosage form throughout the entire time period. In conclusion this in vitro test simulates typical gastric conditions before stomach emptying and indicates drug/shellac particle stability until passage to the gut where drug dissolution can occur.

FIG. 7 depicts SEM images evaluating microsphere attachment to shellac particulars over time during period of shaking. (A) after 15 minutes; (B) after 30 minutes; (C) after 45 minutes; and (D) after 60 minutes of shaking. These results suggest the improved stability for a novel enteric delivery formulation for CRC-015 and other drug APIs using the methods and processes described in the present invention.

VI. Evaluation of drug microspheres and subsequent formation on tissues

An in vivo experiment to further investigate microsphere forming properties of drug dissolved in ethanol and deposited onto mouse jugular artery tissue was conducted. A mouse was placed under general anesthesia and the jugular vein was surgically exposed. CRC-015 (25 mg/mL) was dissolved in ethanol and 2 mΐ solution was deposited onto the jugular vein tissue with ambient temperature air drying for approximately one minute to allow for drug microsphere formation. Vein tissues were surgically removed and examined by SEM. FIG. 8 shows SEM imaging of the resulting CRC-015 drug microspheres on dissected mouse jugular vein tissue. An experiment to further investigate microsphere forming properties of drug dissolved in ethanol and deposited onto previously frozen porcine peripheral artery tissue was conducted. Porcine peripheral artery tissue was harvested and stored at -80 degrees Celsius. On the day of experiment, porcine peripheral artery tissue was thawed at ambient temperature, rinsed with deionized water and cleaned of any fat or fascia tissues. CRC-015 (25 mg/mL) was dissolved in ethanol and 5 pi solution was deposited directly onto the exterior surface of porcine peripheral artery tissue with drying to allow for drug microsphere formation and then examined by SEM. FIG. 9 shows SEM imaging of the resulting CRC-015 drug microspheres on the exterior surface of the collapsed porcine peripheral artery tissue and FIG. 10 shows zoomed image of resulting drug microspheres.

An experiment to further investigate properties of drug dissolved in methanol and directly deposited onto previously frozen porcine peripheral artery tissue was conducted. Porcine peripheral artery tissue was harvested and stored at -80 degrees Celsius. On day of experiment, porcine peripheral artery tissue thawed at ambient temperature, rinsed with deionized water and cleaned of any fat or fascia tissues. CRC-015 (25 mg/mL) was dissolved in methanol and 5 mΐ solution was deposited directly onto the exterior surface of the peripheral artery tissue with drying to allow for drug microsphere formation and then examined by SEM. FIG. 11 shows SEM imaging of the resulting CRC-015 drug microspheres from the methanol formulation on porcine peripheral artery tissue and FIG. 12 shows zoomed image of resulting drug microspheres.

The inventions illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the future shown and described or any portion thereof, and it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions herein disclosed can be resorted by those skilled in the art, and that such modifications and variations are considered to be within the scope of the inventions disclosed herein. The inventions have been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the scope of the generic disclosure also form part of these inventions. This includes the generic description of each invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised materials specifically resided therein.

In addition, where features or aspects of an invention are described in terms of the Markush group, those schooled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. It is also to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of ordinary skill in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent publications, are incorporated herein by reference.

It will be apparent to those skilled in the art that numerous modifications and variations of the described examples and embodiments are possible in light of the above teaching. The disclosed examples and embodiments may include some or all of the features disclosed herein. Therefore, it is the intent to cover all such modifications and alternate embodiments as may come within the true scope of this invention.

Claims

CLAIMS What is claimed is:

1. A method of forming a microspherical hydrophobic material onto at least one substrate, comprising: (a) providing a drug composition; (b) solubilizing the drug composition in at least one solvent; and (c) applying the resultant mixture of step (b) directly to a surface of the at least one substrate.

2. The method of claim 1, wherein the drug is a macrocyclic triene immunosuppressive compound selected from the group consisting of rapamycin (sirolimus), everolimus, zotarolimus, biolimus, novolimus, myolimus, temsirolimus and other compounds having the structure of rapamycin but with a substituent at the carbon corresponding to the 42 or 40 carbon..

3. The method of claim 1 or 2, wherein the forming of the microspherical hydrophobic material occurs during an evaporation stage of the at least one solvent from the surface of the at least one planar substrate.

4. The method of one of the preceding claims, wherein the at least one substrate is a planar substrate.

5. The method of one of the preceding claims, wherein one or more additional drugs are included with the solubilizing of the drug composition in a least one solvent.

6. The method of one of the preceding claims, wherein the at least one substrate is made of a mixed composition.

7. The method of one of the preceding claims, wherein the at least one solvent is a dry solvent.

8. The method of claim 8, wherein the solvent contains less than 7% water.

9. The method of one of the preceding claims, wherein the drug composition is solubilized in at least one solvent in the absence of an excipient.

10. The method of one of the preceding claims, wherein the drug composition in the at least one solvent is in a range of 0.1 to 200 mg/ml.

11. A microspherical hydrophobic material formed the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, has the following structure: where R is C(O)-(CH₂)_n-X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3-8 carbons and optionally contains one or more unsaturated bonds.

12. The microspherical hydrophobic material of claim 11, wherein the material further comprises shellac.

13. The microspherical hydrophobic material of claim 11, wherein the material further comprises paclitaxel.

14. The microspherical hydrophobic material of claim 12 or 13, wherein the ratio between the two compounds varies from 5: 95 by weight to 95:5 by weight.

15. The microspherical hydrophobic material of claim 11, wherein the material consists of the macrocyclic triene immunosuppressive compound, including any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates.