WO2021046200A1

WO2021046200A1 - Stable long-term infusable formulations and methods

Info

Publication number: WO2021046200A1
Application number: PCT/US2020/049173
Authority: WO
Inventors: Ronald J. Shebuski; Heidi MANSOUR; Priyadarshini MURALIDHARAN
Original assignee: Cylerus, Inc.; Arizona Board Of Regents On Behalf Of The University Of Arizona
Priority date: 2019-09-06
Filing date: 2020-09-03
Publication date: 2021-03-11

Abstract

Pharmaceutical formulations and methods of using such formulations are provided wherein the active pharmaceutical ingredient remains stable at normal body temperature for at least about 15, 30, 60, or 90 days. Methods of using such pharmaceutical formulations in implantable, programmable, infusion pumps are provided for long-term treatment of patients.

Description

STABLE LONG-TERM INFUSABLE FORMULATIONS AND METHODS

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND

DEVELOPMENT

[0001] This invention was made with government support under Grant Number

R44AG059279 awarded by the National Institute on Aging Small Business Innovation Research of the National Institutes of Health. The government has certain rights in this invention.

BACKGROUND

[0002] Local dmg delivery in the body remains a challenging problem. While efficacious drugs have been identified and characterized, controlled delivery of such drugs at a sufficient concentration for a sufficient amount of time while avoiding detrimental systemic side effects remains elusive.

[0003] Blood conduits may be constructed of either native arteries or veins, or synthetic materials such as expanded polytetrafluoroethylene (ePTFE) graft material, all of which are frequently used in vascular surgery. Vascular grafts are commonly employed for the creation of arteriovenous (A-V) access used as needle insertion sites to enable blood removal and return for hemodialysis that is performed 2-3 times per week in patients with end stage renal disease (ESRD). More than 75,000 new hemodialysis grafts are placed in the U.S. each year and costs for creating and maintaining these grafts exceed $1 billion annually.

[0004] Vascular grafts are also indicated in the treatment of peripheral vascular disease (PVD) that is the result of atherosclerosis causing arterial obstruction with pain and cramping in the legs, especially below the knee where vessels are smaller. A blood conduit, such as ePTFE or native vein, is often used to bypass the obstructed artery. The durability and long-term patency of blood conduits used to replace diseased arteries in PVD are substantially better than results with ePTFE grafts used to provide chronic blood access for hemodialysis.

[0005] Over 80% of arteriovenous access grafts and 20% of peripheral arterial bypass grafts will fail or become dysfunctional within one year after implantation resulting in considerable patient morbidity and substantial costs to the healthcare system. Dialysis access graft failure is often due to neointimal hyperplasia (i.e., obstructive tissue ingrowth) at the venous outflow tract that is caused by mechanical injury to blood vessels. While drugs that inhibit vascular neointimal

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INCORPORATED BY REFERENCE (RULE 20.6) hyperplasia in these settings are available, delivery of these drugs to the site of injury, at a safe yet effective dose, for a sufficient period of time, has been challenging.

[0006] Maintaining drug stability at the site of injury is difficult for several reasons. First, the drug needs to be stable at body temperature. However, drug stability is typically optimized for storage conditions (refrigeration, freezing) rather than at body temperature. Second, drug stability at body temperature needs to be maintained over extended periods of time. Third, the drug needs to be conveniently delivered to the patient for extended periods of time and provide for easy refill of the drug.

SUMMARY

[0007] Aspects described herein provide pharmaceutical formulations comprising about 1 to about 30% DMSO, about 30 to about 60% propylene glycol, about 30 to about 50% polyethylene glycol, and about 0 to about 10% ethanol. Such formulations can further comprise a drug or active pharmaceutical ingredient (API) (e.g., sirolimus or other olimus drug).

[0008] Further aspects provide an implantable, programmable pump for delivery of the pharmaceutical formulations described herein wherein the pump includes a reservoir having a volume from about 0.5 ml to about 3 ml, the pump being configured to deliver the composition at a dose from about 1 to about 10 mg per month over time period of about 1 to 60 days.

[0009] Additional aspects provide methods method of delivering a pharmaceutical formulation to a patient by filling a drug reservoir in an implantable pump with the pharmaceutical formulations described herein, implanting the pump in the patient wherein the concentration of the drug is from about 1 mg/ml to about 30 mg/ml, the volume of the drug reservoir is from about 0.9 ml to about 3 ml, and configuring the pump to deliver the drug to the patient at a dose of about 1 to about 10 mg/month over a period of time from about 1 to about 60 days until refilling the reservoir.

DETAILED DESCRIPTION

[0010] The following detailed description refers to the description below that illustrates exemplary aspects of the invention. However, the scope of the present invention is not limited to these aspects but is instead defined by the appended claims. Thus, aspects beyond those described below, such as modified versions of the illustrated aspects, may nevertheless be

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INCORPORATED BY REFERENCE (RULE 20.6) encompassed by the present invention.

[0011] Aspects described herein provide pharmaceutical formulations comprising about 1 to about 30% dimethylsulfoxide (DMSO), about 30 to about 60% propylene glycol, about 30 to about 50% polyethylene glycol, and about 0 to about 10% ethanol.

[0012] The term “pharmaceutical formulation” refers to a composition suitable for experimental or clinical use in humans or animals, as approved, for example, by a relevant regulatory agency (e.g., U.S. Food and Drag Administration or FDA). In one aspect, the pharmaceutical formulation contains one or more active pharmaceutical ingredients (API). A pharmaceutical formulation can comprise one or more pharmaceutically acceptable excipients in addition to the API.

[0013] The term “active pharmaceutical ingredient” refers to a pharmaceutical agent or drug intended to have a desirable therapeutic or diagnostic effect in a human or animal. The term “pharmaceutically acceptable excipient” or “excipient” as used herein can refer to an ingredient in the pharmaceutical formulation that does not have a therapeutic or diagnostic effect. As described herein, excipients can serve as carriers for the API and can affect characteristics of the drug (e.g., stability, half-life, pharmacokinetics) and how it is administered to a patient (e.g., route of administration).

[0014] In one aspect, the pharmaceutical formulation can comprise about 20% DMSO, about 50% propylene glycol, and about 30% polyethylene glycol. In another aspect, the pharmaceutical formulation does not contain ethanol.

[0015] In a further aspect, the pharmaceutical formulation comprises about 10% DMSO, about 40% propylene glycol, about 40% polyethylene glycol, and about 10% ethanol. In yet another aspect, the pharmaceutical formulation contains no more than about 10% ethanol.

[0016] The pharmaceutical formulations described herein can further comprise a dmg. In one aspect, the drug inhibits cell growth. In another aspect, the drug inhibits neointimal growth. In another aspect, the drug is selected from the group consisting of one or more olimus drugs (e.g., sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus). In a further aspect, the drug is sirolimus.

[0017] In another aspect, the concentration of the drug (e.g., oli us drug) is at least about 0.5 mg/ml, about 0.5 mg/ml to about 20 mg/ml, or about 10 mg/ml.

[0018] In a further aspect, the drug is stable for at least about 5 to about 60 days at about body

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INCORPORATED BY REFERENCE (RULE 20.6) temperature. The term “stable” refers to the drug concentration in the pharmaceutical formulation remaining at a minimum of about 10, 15, 20, 25, 30, 35, 40, 45, or 50% of the drug’s initial concentration after at least 15, 30, 60 or 90 days. In another aspect, the drug is stable for at least about 10 to about 30 days at normal body temperature (e.g., 37°C +/- 0.25).

[0019] In yet another aspect, the pharmaceutical formulation comprises a parenteral infusible solution.

[0020] The pharmaceutical formulation can comprise about 20% DMSO, about 50% propylene glycol, and about 30% polyethylene glycol and about 10 mg/ml of sirolimus wherein the concentration of sirolimus in the composition is no less than about 80% of the initial concentration after about 30 days at normal body temperature (e.g., 37°C +/- 0.25).

[0021] In one aspect, the pharmaceutical formulation comprises about 10% DMSO, about 40% propylene glycol, about 40% polyethylene glycol, about 10% ethanol, and about 10 mg/ml of sirolimus wherein the concentration of sirolimus in the pharmaceutical formulation is no less than about 50% of the initial concentration after about 90 days at normal body temperature. [0022] Further aspects provide an implantable, programmable pump for delivery of the composition of claim 6, wherein the pump comprises a reservoir having a volume from about 0.5 ml to about 3 ml, the pump being configured to deliver the composition at a dose from about 1 to about 10 mg per month over time period of about 1 to 60 days.

[0023] The term “implantable” refers to being capable of and suitable for insertion inside the body of a human or animal. The term “programmable” means being configured to be controlled by computer hardware and software to deliver the drug locally at a desired rate. A programmable pump can also be configured with a wireless device to communicate with a phone, watch, computer or similar device via a suitable wireless protocol (e.g., bluetooth).

[0024] In yet another aspect, the reservoir is refillable (e.g., through a port accessible to healthcare personnel or the patient). In this aspect, when the pharmaceutical formulation in the reservoir is depleted, it can be refilled at a desired interval (e.g., 15, 20, 25, 30, 45, 60, 90 days). [0025] Further aspects provide methods of delivering a pharmaceutical composition to a patient by filling a drug reservoir in an implantable pump with the pharmaceutical formulations described herein (e.g., about 10% DMSO, about 40% propylene glycol, about 40% polyethylene glycol, about 10% ethanol, and about 10/mg/ml of sirolimus), implanting the pump in the patient wherein the concentration of the drug is from about 1 mg/ml to about 30 mg/ml, and the volume

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INCORPORATED BY REFERENCE (RULE 20.6) of the drug reservoir is from about 0.9 ml to about 3 ml. In this aspect, the pump can be configured to deliver the drug to the patient at a dose of about 1 to about 10 mg/month over a period of time from about 1 to about 60 days until refilling the reservoir.

[0026] In one aspect, the drug is selected from the group consisting of sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus. In another aspect, the drug is sirolimus.

[0027] In a further aspect, the concentration of the drug can be from about 5 to about 20 mg/ml. In another aspect, the concentration of the drug is about 10 mg/ml.

[0028] In yet another aspect, the implantable pump is programmable (e.g., to regulate the delivery rate of the composition, communicate with a wireless device etc.).

[0029] The drug sirolimus is included in a therapeutic class of “limus” or “olimus” drugs, including but not limited to sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus. Aspects described herein are applicable to the entire class of olimus agents, and the term “sirolimus” is used merely as one example of an agent in the olimus/limus class. It will be recognized by persons skilled in the art that descriptions herein with regard to sirolimus are applicable to all olimus/limus agents.

[0030] Sirolimus can be referred to by its chemical name

[(IS ,3R,4R)-4-hydroxy-3 -methoxycyclohexyl] - 1 -methylethyl]- 10,21 -dimethox-y- 6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,l-c][l,4]oxaazacycloh-entriacontine- l,5,ll,28,29(4H,6H,31H)-pentone, its molecular formula C51H79NO13 and has a molecular weight of 914.2. The chemical structure of sirolimus is as follows:

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INCORPORATED BY REFERENCE (RULE 20.6) [0031] The related pharmaceutical “olimus” molecules are relatively similar in chemical structure, behavior, and therapeutic effect. The related molecules typically differ by replacing the hydroxyl group (circled in dashed line in the image above) with other “R” groups. Graziani, et. al., Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs, Nat. Prod. Rep., 2009, 26, 602-609.

Everolimus

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INCORPORATED BY REFERENCE (RULE 20.6)

Deferolimus

[0032] Sirolimus and related “olimus” drugs can be used therapeutically to inhibit neointimal growth that is stimulated by vascular access. Excessive neointimal growth can restrict blood flow and lead to blood clotting and thrombosis in blood vessels (i.e., neointimal hyperplasia).

[0033] Sirolimus and related olimus drugs have been difficult to use in formulation due to their high hydrophobicity and insolubility in aqueous environments. Thus, parenteral formulations for sirolimus and related olimus drugs have generally not been available.

[0034] Moreover, most pharmaceutical formulations are maintained at refrigerated or freezing temperatures until they are ready to be used in order to maximize stability of the API. In contrast, the pharmaceutical formulations described herein can be used for extended periods of time (e.g.,

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INCORPORATED BY REFERENCE (RULE 20.6) up to about 90 days) at body temperature while substantially maintaining the stability of the drug (e.g., sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus). For example, the concentration of sirolimus or olimus drug is substantially maintained over a long period of time in order to provide the drug on an ongoing basis for local delivery to the patient through an implantable pump [0035] In this manner, compliance with continuous treatment with the drug over a desired period of time (e.g., 15-90 days) can be more readily assured. In this example, the patient can return to a healthcare provided on a bi-weekly, monthly, bi-monthly or even every three months to have the supply of the pharmaceutical formulation replenished in the reservoir of an implantable pump. [0036] Exemplary pharmaceutical formulations include at least the following:

Table 1 - Formulation A (Sirolimus (10 mq/rnU)

‘Formulation samples were diluted 10,000 fold

‘Formulation samples were prepped against a neat curve

[0037] Table 1 provides stability data over time (0-90 days) at body temperature for Formulation A expressed as the mean concentration (mg/ml) of sirolimus in the formulation. As shown in Table 1, the mean concentration of sirolimus in Formulation A is maintained entirely through Day 15, is at least about 80% (e.g., 83.5%) of the initial concentration of 11.5 mg/ml by Day 30, at least about 70% (e.g., 70.4) by Day 60, and at least about 40% (e.g., 37.6%) by Day 90.

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INCORPORATED BY REFERENCE (RULE 20.6) Table 2 - Formulation B (Sirolimus - 10 mq/mL)

‘Formulation samples were diluted 10,000- fold

‘Formulation samples were prepped against a neat curve

[0038] Table 2 provides stability data over time (0-90 days) at body temperature for Formulation B expressed as the mean concentration (mg/ml) of sirolimus in the formulation. As shown in Table 2, the mean concentration of sirolimus in Formulation A is at least about 83% of the initial concentration of 12.9 mg/ml through Day 15 (e.g., 82.9%), at least about 65% (e.g., 65.2%) of the initial concentration by Day 30, about the same as Day 30 by Day 60, and at least about 55% (e.g., 55.3%) by Day 90.

[0039] It is understood that the above exemplary formulations can be modified without departing from aspects described herein depending on the desired concentration of the API, to maximize shelf life, to maximize stability at body temperature, etc. For example, pharmaceutical formulations can have from 1 to about 30% dimethylsulfoxide (DMSO), about 30 to about 60% propylene glycol, about 30 to about 50% polyethylene glycol, and about 0 to about 10% ethanol. [0040] In one example, a patient can receive a suitable implantable pump as described herein with a reservoir filled with an amount of Formulation A or Formulation B suitable for administration by the implantable pump over a thirty day time period. The drug can be delivered slowly and in a high concentration (e.g., 10 mg/ml) in a small volume (e.g., 0.9 to about 3 ml) at

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INCORPORATED BY REFERENCE (RULE 20.6) a rate of 10 mg per month before the reservoir is refilled. In this manner, the patient is receiving a constant but small dose of the drug to inhibit neointimal hyperplasia consistently to maintain blood vessel patency and prevent vascular graft failure. This is not only easier for the patient; it improves outcomes and reduces costs associated with graft failure.

[0041] In each of the above exemplary pharmaceutical formulations, sirolimus can be replaced, for example, with an olimus drug (e.g., sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus).

[0042] Excipients such as long-term stabilization of the active ingredient, bulking up a solid formulation that includes potent active ingredient(s), and/or conferring a therapeutic enhancement on the active ingredient in the final dosage form (e.g., facilitating drug absorption, reducing viscosity, and/or enhancing solubility). An excipient may be useful in the manufacturing process to aid in the handling of an active substance, for example, by facilitating powder flowability or non-stick properties. Use of an excipient may increase in vitro stability, for example, by inhibiting (e.g., preventing) denaturation and/or aggregation over the expected shelf life of an active ingredient.

[0043] It will be recognized that the co-solvents herein may be combined in any suitable percentages. It will be further recognized that the therapeutic formulation may include co- solvents) in addition to those described herein. The selection of appropriate co-solvents may depend on any of variety of factors, including but not limited to the long-term stability of the therapeutic agent (e.g., olimus), the route of administration, the dosage form, and the active ingredient. For example, the combination of co-solvent may be selected for stability at 4°C with increased shelf life, and at body temperature, and/or at room temperature for at least a designated period of time (e.g., at least one month, at least three months, at least six months, or at least one year).

[0044] In another example, the pharmaceutical formulation can further comprise a combination of therapeutic agents instead of or in addition to sirolimus or other “olimus” drug (e.g., actimune, paclitaxel, brentuximab, vedotin, pemetrexed, bevacizumab, pegylated liposomal, doxorubicin, carboplatin, cisplatin, oxaliplatin, cetuximab, gemcitabine, eribulin, mesylate, trastuzumab, cabazitaxel, emtansine, pembrolizumab, carfilzomib, nivolumab, pertuzumab, rituximab, paclitaxel, docetaxel, temsirolimus, bedamustine, panitumumab, bortezomib, venofer, zoledronic acid, thiazolidinediones, glipizide, glimepiride, metformin, victoza, or jardiance, at least one

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INCORPORATED BY REFERENCE (RULE 20.6) chemotherapy drug, at least one pain reliever, at least one nutrient, or at least one agent to treat at least one of diabetes, arthritis, cancer, dehydration, or a migraine.

[0045] Various embodiments of the invention have been described above. Although this invention has been described with reference to these specific embodiments, the descriptions are provided for illustrative purposes and are not intended to be limiting. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. For instance, various modifications and applications may occur to those skilled in the art without departing from the scope of the invention as defined by the following claims.

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INCORPORATED BY REFERENCE (RULE 20.6)

Claims

What is claimed is:

1. A pharmaceutical formulation comprising about 1 to about 30% DMSO, about 30 to about 60% propylene glycol, about 30 to about 50% polyethylene glycol, and about 0 to about 10% ethanol.

2. The pharmaceutical formulation of claim 1, comprising about 20% DMSO, about 50% propylene glycol, and about 30% polyethylene glycol.

3. The pharmaceutical formulation of claim 2, wherein the pharmaceutical formulation does not contain ethanol.

4. The pharmaceutical formulation of claim 1, comprising about 10% DMSO, about 40% propylene glycol, about 40% polyethylene glycol, and about 10% ethanol.

5. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation contains no more than about 10% ethanol.

6. The pharmaceutical formulation of claims 1, 2, or 4, further comprising a drug.

7. The pharmaceutical formulation of claim 6, wherein the drug inhibits cell growth.

8. The pharmaceutical formulation of claim 7, wherein the drug inhibits neointimal growth.

9. The pharmaceutical formulation of claim 8, wherein the drug is selected from the group consisting of one or more olimus drugs.

10. The pharmaceutical formulation of claim 9, wherein the drug is selected from the group consisting of one or more of sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus.

11. The pharmaceutical formulation of claim 10, wherein the drug is sirolimus.

12. The pharmaceutical formulation of claim 9, wherein a concentration of the drug is at least about 0.5 mg/ml.

13. The pharmaceutical formulation of claim 12, wherein the concentration of the drug is from about 0.5 mg/ml to about 20 mg/ml.

14. The pharmaceutical formulation of claim 13, wherein the concentration of the drug is about 10 mg/ml.

15. The pharmaceutical formulation of claim 9, wherein the drug is stable for at least about 5 to about 60 days at about body temperature.

16. The pharmaceutical formulation of claim 15, wherein the drug is stable for at least about 10 to about 30 days at about body temperature.

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INCORPORATED BY REFERENCE (RULE 20.6)

17. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation comprises a parenteral infusible solution.

18. The pharmaceutical formulation of claim 1, comprising about 20% DMSO, about 50% propylene glycol, and about 30% polyethylene glycol and about 10 mg/ml of sirolimus wherein a concentration of sirolimus in the pharmaceutical formulation is no less than about 80% of the initial concentration after about 30 days at body temperature.

19. The pharmaceutical formulation of claim 1, comprising about 10% DMSO, about 40% propylene glycol, about 40% polyethylene glycol, about 10% ethanol, and about 10/mg/ml of sirolimus wherein a concentration of sirolimus in the pharmaceutical formulation is no less than about 50% of an initial concentration after about 90 days at body temperature.

20. An implantable, programmable pump for delivery of the pharmaceutical formulation of claim 6, wherein the pump comprises a reservoir having a volume from about 0.5 ml to about 3 ml, the pump being configured to deliver the pharmaceutical formulation at a dose from about 1 to about 10 mg per month over time period of about 1 to 60 days.

21. The pump of claim 15, wherein the reservoir is refillable.

22. A method of delivering a pharmaceutical formulation to a patient comprising filling a drug reservoir in an implantable pump with the pharmaceutical formulation of claim 6, implanting the pump in the patient wherein a concentration of the drug in the pharmaceutical formulation is from about 1 mg/ml to about 30 mg/ml, the volume of the drug reservoir is from about 0.9 ml to about 3 ml, and wherein the pump is configured to deliver the drug to the patient at a dose of about 1 to about 10 mg/month over a period of time from about 1 to about 60 days until refilling the reservoir.

23. The method of claim 17, wherein the drug is selected from the group consisting of sirolimus, everolimus, zotarolimus, tacrolimus, pimecrolimus, temsirolumus, ridaforolimus, deferolimus or biolimus.

24. The method of claim 18, wherein the drug is sirolimus.

25. The method of claim 19, wherein the concentration of the drug is about 5 to about 20 mg/ml.

26. The method of claim 20, wherein the concentration of the drug is about 10 mg/ml.

27. The method of claim 17 wherein the implantable pump is programmable.

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INCORPORATED BY REFERENCE (RULE 20.6)

28. The method of claim 22, wherein the implantable pump can be programmed to regulate the delivery rate of the composition.

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INCORPORATED BY REFERENCE (RULE 20.6)