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EP-3773730-B1 - DRUG DELIVERY FORMULATIONS

EP3773730B1EP 3773730 B1EP3773730 B1EP 3773730B1EP-3773730-B1

Inventors

  • SAILOR, MICHAEL J.
  • HOLLETT, Geoffrey Ian
  • INGALLINERA, Thomas

Dates

Publication Date
20260513
Application Date
20190326

Claims (13)

  1. A drug delivery formulation comprising: a porous silicon material loaded with a meltable composition, wherein the meltable composition comprises a therapeutic agent and a melting point suppression agent, wherein the therapeutic agent is a contraceptive drug selected from the group consisting of segesterone, etonogestrel, levonorgestrel, levonorgestrel butanoate, and medroxyprogesterone acetate, and wherein the melting point suppression agent is a steroid or a polyketide, wherein the meltable composition has a melting temperature, wherein the therapeutic agent has a melting temperature and a decomposition temperature, and wherein the melting temperature of the meltable composition is lower than the melting temperature of the therapeutic agent and the decomposition temperature of the therapeutic agent.
  2. The formulation of claim 1, wherein the formulation is prepared by melt casting the composition into the porous silicon material at a temperature above the melting temperature of the composition and below the decomposition temperature of the therapeutic agent.
  3. The formulation of claim 1, wherein the meltable composition is a eutectic mixture; preferably, wherein the eutectic mixture has a eutectic temperature that is below the decomposition temperature of the therapeutic agent.
  4. The formulation of claim 1, wherein the melting temperature of the therapeutic agent is no more than 50 °C, 20 °C, 10 °C, 5 °C, 2 °C, or 1 °C lower than the decomposition temperature of the therapeutic agent; and/or, wherein the melting temperature of the meltable composition is at least 1 °C, 2 °C, 5 °C, 10 °C, 20 °C, or 50 °C lower than the decomposition temperature of the therapeutic agent.
  5. The formulation of claim 1, wherein the melting point suppression agent is (i) cholesterol or (ii) rapamycin.
  6. The formulation of claim 1, wherein the melting point suppression agent is a steroid; preferably, wherein the therapeutic agent is levonorgestrel, and the melting point suppression agent is cholesterol.
  7. The formulation of claim 1, wherein the porous silicon material is loaded to at least 20%, at least 40%, or at least 70% weight/weight with the meltable composition; or, wherein the porous silicon material has a porosity of at least 35%, at least 55%, at least 75%, or from 15% to 85%.
  8. The formulation of claim 1, wherein the formulation releases the therapeutic agent into an aqueous solution more slowly than the therapeutic agent is released from a formulation comprising the porous silicon material loaded with the therapeutic agent without the melting point suppression agent.
  9. The formulation of claim 1, wherein the porous silicon material is an oxidized porous silicon material; preferably, wherein the porous silicon material has been oxidized at a temperature of 800 °C or greater for 1 hour or longer.
  10. The formulation of claim 1, wherein the porous silicon material is a particulate material; preferably, wherein the particulate material has an average diameter or length of from 10 nm to 100 µm.
  11. A pharmaceutical composition comprising the drug delivery formulation of any one of claims 1-10 and a pharmaceutically acceptable carrier.
  12. The drug delivery formulation according to any one of claims 1-10 or the pharmaceutical composition according to claim 11, for use in preventing pregnancy in a human female subject in need thereof; preferably, wherein the human female subject is in need of contraception; optionally, wherein the drug delivery formulation or pharmaceutical composition is for parenteral administration; preferably, wherein the drug delivery formulation or pharmaceutical composition is for subcutaneous administration.
  13. The drug delivery formulation or pharmaceutical composition for use according to claim 12, wherein the therapeutic agent of the drug delivery formulation or pharmaceutical composition is released in the human female subject for an extended time period; preferably, wherein the therapeutic agent is released in the human female subject for at least 60 days.

Description

TECHNICAL FIELD The disclosure provides drug delivery formulations that comprise a porous silicon material loaded with a meltable compound or composition. The meltable compositions comprise a melting point suppression agent. The disclosure further provides methods of making said drug delivery formulations and uses thereof. BACKGROUND Formulations suitable for the controlled delivery of active therapeutic agents over long periods of time continue to be a subject of intense interest and effort in the pharmaceutical and therapeutic sciences. In particular, the long-term delivery of therapeutic agents having low solubility in aqueous solutions can be especially difficult. One area where the development of formulations to provide long-term delivery of a therapeutic agent is of particular importance is in the delivery of birth control agents. Access to reliable and safe contraception is a critical component to lowering maternal death rates while simultaneously granting women agency over their lives. Effective family planning tools have been linked to positive health outcomes, but they also have the societal benefit of increasing women's participation in the workforce and enrollment in professional and graduate level training. Currently, however, there are large populations of women who wish to use contraception but ultimately do not. According to the World Health Organization's (WHO) 2015 report on Trends in Contraceptive Use Worldwide, 12% of married or in-union women between the ages of 15 and 49 had unmet contraceptive needs. In addition, it is estimated that over 500,000 women die each year from pregnancy-related complications. Subcutaneous or intramuscular injection of a long-acting drug formulation is a large and growing approach to contraception - it is the form most widely used in sub-Saharan Africa, at more than double the rate of its next highest competitor, the daily oral pill (10.7% vs 5.1%). By far, the most popular injection is depot medroxyprogesterone acetate (DMPA, Depo-Provera®), with over 30 million doses procured by the United Nations Population Fund in 2015. Since its release in 1960, there have been minimal innovations in the field of injectable contraceptives despite the obvious drawbacks of DMPA. In the United States, the Food and Drug Administration has stipulated a "black box" warning label on DMPA, noting that women who use DMPA may experience significant bone mineral density loss over time. Oral formulations of MPA (Provera®) do not carry the same warning label, and some doctors have expressed concern that the label limits access to an important tool for women's health. There have been few innovations in the field of injectable contraceptives apart from modifications in drug (norethisterone enanthate, NET-EN), or packaging (SayanaPress®), and the field has relied on the same depot injection of a pure crystalline drug for more than 50 years. By contrast, diseases such as cancer, bipolar disorder, and type 2 diabetes have all seen improved patient outcomes by switching from crystalline drug injections to host material formulations that can better control the pharmacokinetic profile of the drug. Given the number of women who use injectable contraception and its impact on maternal morbidity and mortality, it is surprising that there has been little improvement on DMPA. Extended release profiles for contraceptive drugs have been successfully observed in implants such as Norplant®, but they require doctor supervision for implantation and removal and cannot be self-administered by the patient. The two most important issues with DMPA injections relate to the pharmacokinetic profile: there is an initial excessive burst of MPA in the serum, and MPA concentration drops very slowly at the end of the intended dose period. To ensure sufficiently long action of the contraceptive, the injected dose is quite large, and the high MPA concentration during the weeks following injection (the burst release phase) is largely responsible for bone mineral density loss. The long tail is an issue for many women timing their return to fertility. One study found that the median return to fertility for DMPA users was approximately 9 months post-injection, which is nearly three times longer than the intended 3-month coverage indicated for DMPA. In extreme cases, ovulation did not return for more than 10 months after DMPA was supposed to have cleared from the body. Traditional approaches for extending drug release utilize polymer-based materials, such as poly(lactic-co-glycolic) acid (PLGA). This strategy has seen success in a variety of treatments with products such as Risperdal Consta® (bipolar disorder), Sandostatin LAR® (carcinoid syndrome), and Bydureon® (type 2 diabetes). By incorporating the drug into a host material, the surface area of exposed drug is minimized and the drug is only released when the polymer dissolves. While microsphere hosts provide longer duration of drug delivery, their release profiles sho