Mineral coated microparticles for sustained delivery of bioactive molecules
阅读说明：本技术 用于持续递送生物活性分子的矿物质涂覆微粒 (Mineral coated microparticles for sustained delivery of bioactive molecules ) 是由 W·墨菲 A·克莱门茨 C·张伯伦 R·范德比 于 2018-04-03 设计创作，主要内容包括：公开了用于提供活性剂的制剂。制剂包括包含活性剂和矿物质涂覆微粒的载体,其中活性剂吸附到所述矿物质。其他制剂包括包含矿物质涂覆微粒的载体,其中矿物质涂覆微粒包含活性剂。还公开了持续递送活性剂的方法和使用提供持续递送活性剂的制剂治疗炎性疾病的方法。(Formulations for providing active agents are disclosed. The formulation includes a carrier comprising an active agent and mineral-coated particles, wherein the active agent is adsorbed to the mineral. Other formulations include a carrier comprising mineral coated particles, wherein the mineral coated particles comprise an active agent. Also disclosed are methods of sustained delivery of active agents and methods of treating inflammatory diseases using formulations that provide sustained delivery of active agents.)
1. A formulation for providing an active agent, comprising:
a vector, wherein the vector comprises
At least a first active agent; and
a mineral-coated particulate comprising a mineral coating; and at least a second active agent.
2. The formulation of claim 1, wherein the second active agent is adsorbed to the mineral coating.
3. The formulation of claim 1, wherein the second active agent is the same as the first active agent in the carrier.
4. The formulation of claim 1, wherein the second active agent adsorbed to the mineral coating is different from the active agent in the carrier.
5. The formulation of claim 1, wherein the first active agent and the second active agent are adsorbed to the mineral coating.
6. The formulation of claim 1, wherein the first active agent and the second active agent are an IL-1 antagonist, an IL-1F2 antagonist, an IL-1F3 antagonist, an IL-1F4 antagonist, an IL-1F5 antagonist, an IL-1F6 antagonist, an IL-1F7 antagonist, an IL-1F8 antagonist, an IL-1F9 antagonist, an IL-1F10 antagonist, an IL-1F11 antagonist, an IL-1R antagonist, abatacept, rituximab, tositumomab, anakinumab, etanercept, infliximab, seituzumab, golimumab, and combinations thereof.
7. The formulation of claim 6, wherein the IL-1 antagonist is a recombinant IL-1 antagonist.
8. The formulation of claim 1, wherein the mineral coating comprises calcium, phosphate, carbonate, and combinations thereof.
9. The formulation of claim 1, wherein the mineral coating further comprises a halogen.
10. The formulation of claim 9, wherein said halogen is selected from the group consisting of fluorine, chlorine, bromine, iodine, astatine, and combinations thereof.
11. The formulation of claim 1, wherein the mineral-coated particulate comprises a core selected from the group consisting of polymers, ceramics, metals, glasses, and combinations thereof.
12. The formulation of claim 1, wherein said second active agent is incorporated into said mineral coating.
13. The formulation of claim 1, wherein the carrier comprises at least one of the first active agent or the second active agent.
14. The formulation of claim 1, wherein the second active agent is adsorbed to the mineral coating, incorporated into the mineral coating, and combinations thereof.
15. The formulation of claim 1, wherein the mineral-coated particulate comprises a multi-layer mineral coating.
16. The formulation of claim 15, wherein the layers of the mineral coating have the same mineral composition.
17. The formulation of claim 15, wherein the layers of the mineral coating have different mineral compositions.
18. The formulation of claim 15, wherein the second active agent is adsorbed into the layer of the mineral coating, incorporated into the layer of the mineral coating, and combinations thereof.
19. A method for sustained delivery of at least one active agent, the method comprising:
administering a formulation comprising a carrier, wherein the carrier comprises
At least a first active agent; and
a mineral-coated particulate comprising a mineral coating; and at least a second active agent.
20. The method of claim 19, wherein the second active agent is adsorbed to the mineral coating.
21. The method of claim 19, wherein the second active agent adsorbed to the mineral coating is the same as the active agent in the carrier.
22. The method of claim 19, wherein the second active agent adsorbed to the mineral coating is different from the first active agent in the carrier.
23. The method of claim 19, wherein the first active agent and the second active agent are adsorbed to the mineral coating.
24. The method of claim 19, wherein the first active agent and the second active agent are an IL-1 antagonist, an IL-1F2 antagonist, an IL-1F3 antagonist, an IL-1F4 antagonist, an IL-1F5 antagonist, an IL-1F6 antagonist, an IL-1F7 antagonist, an IL-1F8 antagonist, an IL-1F9 antagonist, an IL-1F10 antagonist, an IL-1F11 antagonist, an IL-1R antagonist, abatacept, rituximab, tositumomab, anakinumab, etanercept, infliximab, seituzumab, golimumab, and combinations thereof.
25. The method of claim 24, wherein the IL-1 antagonist is a recombinant IL-1 antagonist.
26. The method of claim 19, wherein the mineral coating comprises calcium, phosphate, carbonate, and combinations thereof.
27. The method of claim 19, wherein the mineral coating further comprises a halogen.
28. The method of claim 19, wherein the mineral-coated particulate comprises a core selected from the group consisting of polymers, ceramics, metals, glasses, and combinations thereof.
29. The method of claim 19, wherein the second active agent is incorporated into the mineral coating.
30. The method of claim 19, wherein the carrier comprises at least one of the first active agent and the second active agent.
31. The method of claim 19, wherein the second active agent is adsorbed to the mineral coating, incorporated into the mineral coating, and combinations thereof.
32. The method of claim 19, wherein the mineral-coated particulate comprises a multi-layer mineral coating.
33. The method of claim 32, wherein the layers of the mineral coating have the same mineral composition.
34. The method of claim 32, wherein the layers of mineral coating have different mineral compositions.
35. The method of claim 32, wherein the second active agent is adsorbed into the layer of the mineral coating, incorporated into the layer of the mineral coating, and combinations thereof.
36. A method of treating an inflammatory disease in a subject in need thereof, the method comprising:
administering a formulation to the subject, wherein the formulation comprises a carrier, wherein the carrier comprises at least a first active agent; and
mineral coated particles comprising
A mineral coating; and
at least a second active agent.
37. The method of claim 36, wherein the second active agent is adsorbed to the mineral coating.
38. The method of claim 36, wherein the second active agent and the first active agent are the same active agent.
39. The method of claim 36, wherein said second active agent and said first active agent are different.
40. The method of claim 36, wherein the first active agent and the second active agent are selected from the group consisting of IL-1 antagonists, IL-1F2 antagonists, IL-1F3 antagonists, IL-1F4 antagonists, IL-1F5 antagonists, IL-1F6 antagonists, IL-1F7 antagonists, IL-1F8 antagonists, IL-1F9 antagonists, IL-1F10 antagonists, IL-1F11 antagonists, IL-1R antagonists, abatacept, rituximab, tositumomab, anakinumab, etanercept, infliximab, seituzumab, golimumab, and combinations thereof.
41. The method of claim 40, wherein the IL-1 antagonist is a recombinant IL-1 antagonist.
42. The method of claim 36, wherein the mineral coating comprises calcium, phosphate, carbonate, and combinations thereof.
43. The method of claim 36, wherein the mineral coating further comprises a halogen.
44. The method of claim 36, wherein the mineral-coated particulate comprises a core selected from the group consisting of polymers, ceramics, metals, glasses, and combinations thereof.
45. The formulation of claim 36, wherein said second active agent is incorporated into said mineral coating.
46. The formulation of claim 36, wherein the carrier comprises one or more active agents.
47. The method of claim 36, wherein the second active agent is adsorbed to the mineral coating, incorporated into the mineral coating, and combinations thereof.
48. The method of claim 36, wherein the mineral-coated particulate comprises a multi-layer mineral coating.
49. The method of claim 48, wherein the layers of the mineral coating have the same mineral composition.
50. The method of claim 48, wherein the layers of mineral coating have different mineral compositions.
51. The method of claim 48, wherein the second active agent is adsorbed into the layer of the mineral coating, incorporated into the layer of the mineral coating, and combinations thereof.
52. A mineral-coated particulate comprising an active agent, wherein the active agent is adsorbed to the mineral, incorporated into the mineral, and combinations thereof.
53. The mineral-coated particle of claim 52, further comprising a core.
54. The mineral-coated particulate of claim 52, wherein the core is selected from the group consisting of polymers, ceramics, metals, glasses, and combinations thereof.
55. The mineral-coated particle of claim 52, wherein the mineral coating comprises calcium, phosphate, carbonate, and combinations thereof.
56. The mineral-coated particulate of claim 52, wherein the mineral coating further comprises a halogen.
57. The mineral-coated particle of claim 52, wherein the mineral-coated particle comprises a multi-layer mineral coating.
58. The mineral-coated particle of claim 57, wherein the layers of the mineral coating have the same mineral composition.
59. The mineral-coated particle of claim 57, wherein the layers of the mineral coating have different mineral compositions.
60. The mineral-coated particulate of claim 57, wherein the second active agent is adsorbed into the layer of the mineral coating, incorporated into the layer of the mineral coating, and combinations thereof.
61. A method of treating post-surgical inflammation in a subject in need thereof, the method comprising administering a formulation to the subject, wherein the formulation comprises a carrier comprising an active agent and a mineral-coated particulate, wherein the mineral-coated particulate comprises an active agent.
62. The method of claim 61, wherein the active agent is selected from the group consisting of an IL-1 antagonist, an IL-1F2 antagonist, an IL-1F3 antagonist, an IL-1F4 antagonist, an IL-1F5 antagonist, an IL-1F6 antagonist, an IL-1F7 antagonist, an IL-1F8 antagonist, an IL-1F9 antagonist, an IL-1F10 antagonist, an IL-1F11 antagonist, an IL-1R antagonist, abatacept, rituximab, tolizumab, anakinra, adalimumab, etanercept, infliximab, certolizumab, golimumab, and a combination thereof.
Brief description of the invention
In one aspect, the invention relates to a formulation for providing an active agent. The formulation comprises a carrier, wherein the carrier comprises at least a first active agent; and mineral coated particles comprising a mineral coating; and at least a second active agent. In one embodiment, the second active agent is adsorbed to the mineral. In one embodiment, the second active agent is incorporated into the mineral. In one embodiment, the second active agent is both adsorbed to and incorporated into the mineral.
In one aspect, the present invention relates to a formulation for providing an active agent. The formulation includes a carrier, wherein the carrier includes a mineral-coated particulate comprising an active agent adsorbed to the mineral.
In one aspect, the present invention relates to formulations for the sustained delivery of active agents. The formulation includes a solution having a first active agent; and mineral coated particles added to the solution with the first active agent. In one embodiment, the active agent adsorbs to the mineral coated particles when added to a solution comprising a first active agent. In another embodiment, a second active agent is incorporated into the mineral coated particles, and the mineral coated particles are then added to a solution of the first active agent.
In one aspect, the present invention relates to a mineral coated particulate comprising an active agent. In one embodiment, the second active agent is adsorbed to the mineral. In one embodiment, the second active agent is incorporated into the mineral. In one embodiment, the second active agent is both adsorbed to and incorporated into the mineral.
In one aspect, the present invention relates to a mineral-coated particle comprising a layered mineral coating and at least one active agent adsorbed on at least one layer of the mineral coating.
In one aspect, the present invention relates to a method for immediate and sustained delivery of an active agent. The method comprises providing to a subject in need thereof a formulation comprising a carrier containing at least a first active agent; and mineral coated particles comprising a mineral coating; and at least a second active agent. In one embodiment, the second active agent is adsorbed to the mineral. In one embodiment, the second active agent is incorporated into the mineral. In one embodiment, the second active agent is both adsorbed to the mineral and incorporated into the mineral.
In one aspect, the invention relates to a method for treating an inflammatory disease in a subject in need thereof. The method comprises administering to the subject a formulation, wherein the formulation comprises a carrier comprising at least a first active agent; and mineral coated particles comprising a mineral coating; and at least a second active agent. In one embodiment, the second active agent is adsorbed to the mineral. In one embodiment, the second active agent is incorporated into the mineral. In one embodiment, the second active agent is both adsorbed to and incorporated into the mineral.
In another aspect, the present disclosure is directed to a method of treating post-surgical inflammation in a subject in need thereof. The method comprises administering a formulation to a subject, wherein the formulation comprises a carrier comprising an active agent and mineral-coated particles, wherein the mineral-coated particles contain the active agent.
Brief Description of Drawings
Fig. 1A is a low-magnification SEM showing the platelet morphology of mineral coated particles formed in 4.2mM (low) carbonate modified simulated body fluid (mSBF). FIG. 1B is a high magnification SEM showing the platy morphology of mineral coated particles formed in 4.2mM (low) carbonate mSBF. Figure 1C is a low-magnification SEM showing the spherulitic morphology of mineral coated particles formed in 25mM (medium) carbonate mSBF. FIG. 1D is a high magnification SEM showing the spherulitic morphology of mineral coated particles formed in 25mM (medium) carbonate mSBF. FIG. 1E is a low-magnification SEM showing the spherulitic morphology of mineral coated particles formed in 100mM (high) carbonate mSBF. FIG. 1F is a high magnification SEM showing the spherulitic morphology of mineral coated particles formed in 100mM (high) carbonate mSBF. FIG. 1G illustrates the use of low HCO3 -mSBF (●), medium HCO3 -mSBF (. tangle-solidup.) and high HCO3 -Calcium release from mineral coated microparticles formed by mSBF (xxx). FIG. 1H is a schematic representation of BMP-2 with low HCO3 -mSBF, medium HCO3 -mSBF and high HCO3 -Incorporation of mineral coated particles formed by mSBF. FIG. 1I illustrates the synthesis of a compound with low HCO3 -mSBF (■), medium HCO3 -mSBF (●) and high HCO3 -mineral coated microparticles formed with mSBF (solidup) release BMP-2.
Figure 2A illustrates the combination of IL-Ra with different formulations of mineral coated microparticles (e.g., high carbonate microparticles and low carbonate microparticles) and different concentrations of active agent in the incubation solution.
Figure 2B illustrates IL-Ra binding efficiency of carbonate microparticles and low carbonate microparticles with different concentrations of active agent in incubation solution.
Figure 3 illustrates the sustained release of IL-Ra by mineral coated microparticles over 7 days.
FIG. 4A is a graph depicting IL-Ra released from mineral coated microparticles is active and inhibits IL-1 stimulated macrophage production of IL-6. Shows the concentration of IL-6 produced by macrophages incubated with 4.2mM mineral coated microparticles containing IL-Ra, 100mM mineral coated microparticles containing IL-Ra, soluble IL-Ra, unloaded microparticles and no IL-Ra for 12 hours after stimulation with IL-1.
FIG. 4B is a graph depicting IL-Ra released from mineral coated microparticles is active and inhibits IL-1 stimulated macrophage production of IL-6. Media concentrations of IL-6 produced by macrophages incubated with 4.2mM mineral coated microparticles containing IL-Ra, 100mM mineral coated microparticles containing IL-Ra, soluble IL-Ra, unloaded microparticles, and no IL-Ra for 24 hours after stimulation with IL-1 are shown.
FIG. 5 is a graph depicting the inhibition of IL-1-induced IL-6 production in vivo when mice received a single subcutaneous injection of PBS, unloaded microparticles, soluble IL-Ra, or IL-Ra microparticles (MP incubated in soluble IL-Ra).
FIG. 6 is a graph depicting the biological activity of IL-Ra released from microparticles in reducing IL-1-induced proliferation of mouse T lymphocytes.
Figure 7 is a time chart of rat MCL healing, consisting of 3 overlapping phases: inflammatory phase, proliferative phase and remodeling phase. The inflammatory phase persists from the day of injury to
Fig. 8A is a Magnetic Resonance Image (MRI) showing different concentrations of intramuscularly injected SPIO-labeled mineral-coated microparticles using T2-weighted MRI, demonstrating that the area of low intensity decreases with decreasing microparticle concentration.
Figure 8B is a Magnetic Resonance Image (MRI) showing SPIO-labeled MCM in healing-phase rat MCL when injected after injury.
Figure 8C is a Magnetic Resonance Image (MRI) showing that MCM remained localized in MCL for at least 15 days after injection.
Figure 9A illustrates up-regulation of M1 macrophages by MCM in
Fig. 9B is an optical micrograph showing that MCM remained localized 7 days after injection in MCL as indicated by alizarin red staining for calcium, but did not affect ligament structure or cause additional edema.
Figure 9C is an optical micrograph showing that MCM is no longer present in
FIGS. 10A-10D show that the amount of IL-Ra bound to MP can be modulated, and that MP releases IL-Ra in a sustained manner. FIG. 10A is a schematic of IL-Ra preparation, which involves adding microparticles to a solution containing IL-Ra, followed by incubation for 1 hour. FIG. 10B depicts the reduction in the amount of IL-Ra bound per mg MP when incubated in reduced IL-Ra concentrations during loading. FIG. 10C depicts that the binding efficiency of IL-Ra to MP increases with decreasing IL-Ra concentration during loading. Figure 10D shows that the cumulative release of IL-Ra from MP in simulated body fluid over 14 days showed sustained release for at least 14 days. Data represent mean + standard error.
FIGS. 11A-11E depict release of IL-Ra from MP that is biologically active in vitro. FIG. 11A shows that after treatment of D10.G4.1 mouse T lymphocytes with IL-1, the cell concentration increased, and that the unloaded MP did not affect the IL-1 induced increase in cell concentration. FIG. 11B shows that IL-1Ra MP significantly reduced cell concentration after IL-1 stimulation of D10.G4.1 mouse T lymphocytes compared to cells treated with soluble IL-Ra or PBS. Figure 11C depicts IL-Ra concentrations in culture media of d10.g4.1 mouse T lymphocytes in media treated with soluble IL-Ra were significantly higher and undetectable in PBS treated media compared to IL-Ra MP. FIG. 11D is a schematic of THP-1 culture with unloaded MP or IL-RAMP in a transwell cell culture system. After 6 hours of treatment, IL-1 was added to the medium. Figure 11E depicts that treatment with IL-Ra MP significantly reduced the media concentration of IL-6 in IL-1 stimulated THP-1
FIGS. 12A-12C are graphs showing that IL-Ra MP increased serum concentrations of IL-Ra for 14 days and inhibited IL-1 activity in vivo. Figure 12A is a diagram of IL-Ra MP in vivo treatment, which involves adding microparticles to an IL-Ra solution, which is then injected. Figure 12B is a graph showing that the concentration of IL-Ra in serum collected 1, 3, 5, 7 and 14 days post-treatment remained elevated for 14 days. FIG. 12C shows serum IL-6 normalized to the serum concentration of IL-6 in PBS-treated animals collected 2 hours after IL-1 stimulation. Values below 1 indicate IL-1-induced reduction of serum IL-6. Different letters represent significant differences between groups (p < 0.05); represents significant differences between treatment and PBS control (p < 0.05). N.d. indicates undetectable.
Figures 13A-13E depict that the MP of the IL-Ra coating binds more IL-Ra, releases IL-Ra at a slower rate, has a lower burst release, and inhibits IL-1 activity in vivo for an extended duration of time. FIG. 13A is a schematic representation of the manufacture of layered IL-Ra MP. FIG. 13B shows that lamellar IL-Ra MP binds more IL-Ra per mg MP than IL-Ra MP. Figure 13C shows that lamellar IL-Ra MP released a lower percentage of loaded IL-Ra after 1 day and released IL-Ra in a sustained manner for at least 14 days compared to IL-Ra MP. FIG. 13D shows that lamellar IL-Ra MP raised serum IL-Ra to the above detectable levels for 10 days. FIG. 13E shows that lamellar IL-Ra MP decreased serum IL-6 concentrations compared to PBS control after IL-1 stimulation for at least 14 days.
14A-14C depict the formation of a particulate coating and IL-Ra loading. Fig. 14A shows SEM of uncoated B-TCP core material at lower (top) and higher (bottom) magnification. Fig. 14B shows the SEM of the particles after 7 days of coating in mSBF at lower (top) and higher (bottom) magnification. FIG. 14C is a schematic of particulate coating formation and IL-Ra loading.
15A-15C depict the local delivery of IL-Ra by microparticles. FIG. 15A depicts tissue concentration of IL-Ra in homogenized MCL. Figure 15B depicts IL-Ra serum concentrations. Figure 15C depicts alizarin red staining of MP in MCL at 7 and 14 days post-treatment. The graphs represent mean ± sem, p <0.05 between soluble IL-Ra and IL-Ra MP, p <0.05 between IL-Ra MP at
FIGS. 16A-16C depict the anti-inflammatory activity of IL-Ra MP. Fig. 16A depicts M1 macrophage concentrations within
Fig. 17A and 17B depict local inflammatory protein concentrations within MCL. FIG. 17A depicts the concentration of IL-1 α, and FIG. 17A depicts the concentration of IL-1 α. Figure 17B depicts the normalized IL-1 β concentration relative to
FIGS. 18A-18C depict in vivo responses to microparticles. Figure 18A depicts H & E staining of
Detailed Description
The present invention relates to formulations for providing active agents. In some embodiments, the formulation includes a carrier comprising an active agent and mineral coated particles, wherein the active agent is adsorbed to the mineral coating. In some embodiments, the formulation includes a carrier comprising an active agent and mineral coated particulates, wherein the active agent is incorporated into the mineral coating. In some embodiments, the formulation includes a carrier comprising an active agent and mineral coated particles, wherein the active agent is incorporated into the mineral coating and the active agent is adsorbed to the mineral coating. The active agent contained in the carrier provides a rapid action upon administration, while the active agent adsorbed to the mineral coating and/or the active agent incorporated into the mineral coating provides sustained delivery as the mineral coating degrades. Also disclosed are methods of sustained release of active agents and methods of treating inflammatory diseases using formulations that provide sustained release of active agents.
In one aspect, the invention relates to a formulation for providing an active agent.
In one embodiment, the formulation comprises a carrier, wherein the carrier comprises an active agent and a mineral coated particulate, wherein the mineral coated particulate comprises a core; a mineral coating on the core; and an active agent adsorbed to the mineral coating.
In one embodiment, the formulation comprises a carrier, wherein the carrier comprises an active agent and a mineral coated particulate, wherein the mineral coated particulate comprises a core; a mineral coating on the core; and an active agent in the mineral coating.
In one embodiment, the formulation comprises a carrier, wherein the carrier comprises an active agent and a mineral coated particulate, wherein the mineral coated particulate comprises a core; a mineral coating on the core; at least one active agent in the mineral coating and at least one active agent adsorbed to the mineral coating.
In one embodiment, the formulation comprises a carrier, wherein the carrier comprises an active agent and a mineral coated particle, wherein the mineral coated particle comprises a core, a first mineral coating on the core, an active agent adsorbed to the first mineral coating, a second mineral coating, and a second active agent adsorbed to the second mineral coating.
In one embodiment, the formulation comprises a carrier, wherein the carrier comprises an active agent and a mineral coated particulate, wherein the mineral coated particulate comprises a core, a multilayer mineral coating, and an active agent. The layers of the mineral coating as described herein can be the same coating formulation. The layers of mineral coating as described herein can also be different coating formulations. After each layer of mineral coating is prepared as described herein, the active agent can be adsorbed onto the layer of mineral coating. The active agent can be incorporated into the layer of the mineral coating during mineral formation, as described herein. The active agents as described herein may be the same active agent. The active agents as described herein may be different active agents.
As used herein, the term formulation generally means that the benefit agent and mineral coated microparticles are formulated, mixed, added, dissolved, suspended, solubilized, formulated into a solution, in or carried by a fluid in a physicochemical form acceptable for parenteral administration, and/or the like.
In one embodiment, the active agent adsorbed to the mineral coating is the same as the active agent in the carrier. In another embodiment, the active agent adsorbed to the mineral coating is different from the active agent in the carrier. In another aspect, at least two different active agents are adsorbed to the mineral coating. Contemplated embodiments also include 3, 4,5, or more different active agents adsorbed to the mineral coating. In one embodiment, the active agent incorporated into the mineral coating is the same as the active agent in the carrier. In another embodiment, the active agent incorporated into the mineral coating is different from the active agent in the carrier. In another aspect, at least two different active agents are incorporated into the mineral coating. Contemplated embodiments also include incorporating 3, 4,5, or more different active agents into the mineral coating. In another aspect, the active agent can be incorporated into the mineral coating in combination with adsorption of the active agent to the mineral coating. The formulation includes 3, 4,5 or more different active agents in a carrier solution.
Particularly suitable active agents may be IL-1 antagonists; an IL-1 receptor antagonist; (iii) acalep; rituximab; (ii) toclizumab; anakinra; adalimumab; etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. Particularly suitable IL-1 antagonists are recombinant IL-1 antagonists. Abatacept (Abatacept) is a fusion protein consisting of the extracellular domain of CTLA-4 with the hinge of IgG1, CH2 and CH3 domains, currently approved for the rheumatoid arthritis population. Rituximab is a monoclonal antibody directed against CD20, CD20 is present predominantly on the surface of B cells of the immune system and is used to treat autoimmune diseases and cancer types. Rituximab has also been approved for use in combination with Methotrexate (MTX) to alleviate signs and symptoms in adult patients with moderate to severe active Rheumatoid Arthritis (RA). Tolizumab (Tocilizumab) is an immunosuppressive drug used mainly in the treatment of Rheumatoid Arthritis (RA) and systemic juvenile idiopathic arthritis, a serious form of arthritis in children. It is a humanized monoclonal antibody directed against the
Other suitable active agents can be antagonists of the cytokine IL-1 family. The IL-1 family is a group of 11 cytokines that induce a complex network of proinflammatory cytokines and regulate and trigger the inflammatory response. These 11 cytokines include IL-1a (IL-1F1), IL1b (IL-1F2), IL-Ra (IL-1F3), IL-18(IL-1F4), IL-36Ra (IL-1F5), IL-36 α (IL-1F6), IL-37(IL-1F7), IL-36 β (IL-1F8), IL36 γ (IL-1F9), IL-38(IL-1F10) and IL-33(IL-1F 11).
Other suitable active agents may be antagonists of the interleukin-1 receptor (IL-1R) family. The IL-1R receptor family is characterized by an extracellular immunoglobulin-like domain and an intracellular Toll/interleukin-1R (TIR) domain. It is a group of structurally homologous proteins found in all species from plants to mammals, and is conserved in all species. IL-1R is involved in immune host defense and hematopoiesis. Type I IL-1R (IL-1RI) (also known as CD121a) is a receptor for IL-1 α, IL-1 β and IL-RA. IL-1R family members include IL-1R1, IL-18R α, IL-Rrp2 and
The unbound active agent contained in the carrier and the active agent adsorbed to the mineral coated particles have an action profile when formulated in one formulation that is the same or substantially the same as the action profile when the unbound active agent and the active agent adsorbed to the mineral coated particles are administered in separate formulations. Thus, administration of unbound active agent as a bolus (bolus administration) has a rapid or immediate profile of action, while bound active agent (adsorbed to mineral coated particles) has a sustained release profile of action.
As used herein, an effective amount, a therapeutically effective amount, a prophylactically effective amount, and a diagnostically effective amount is the amount of unbound active agent and active agent adsorbed to the mineral coated microparticles required to elicit a desired biological response upon administration.
Suitable carriers include water, saline, isotonic saline, phosphate buffered saline, ringer's lactate, and the like.
The formulation may also include other components, such as surfactants, preservatives and excipients. The surfactant may reduce or prevent surface-induced aggregation of the active agent and the mineral coated particles. Various conventional surfactants can be used, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts of about 0.001% to about 4% by weight of the formulation are typical. Pharmaceutically acceptable preservatives include, for example, phenol, o-cresol, m-cresol, p-cresol, methyl paraben, propyl paraben, 2-phenoxyethanol, butyl paraben, 2-phenylethanol, benzyl alcohol, chlorobutanol, thimerosal, bromophenol, benzoic acid, propyleneurea, chlorhexidine, sodium dehydroacetate, chlorocresol, ethyl paraben, benzethonium chloride, chlorobenzenesulfonic acid (3 p-chlorophenoxypropane-1, 2-diol), and mixtures thereof. The preservative may be present at a concentration of about 0.1mg/ml to about 20mg/ml, including about 0.1mg/ml to about 10 mg/ml. The use of preservatives in pharmaceutical compositions is well known to those skilled in the art. For convenience, reference is made to "remington: science and practice of pharmacy, 19 th edition 1995. The formulation may include a suitable buffer, such as sodium acetate, glycylglycine, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) and sodium phosphate. Excipients include components for tonicity adjustment, antioxidants and stabilizers which are commonly used in the preparation of pharmaceutical formulations. Other inactive ingredients include, for example, L-histidine monohydrochloride monohydrate, sorbitol,
Any suitable material may be used as the core on which the mineral coating is formed. Particularly suitable core materials (core materials) are those which are known to be non-toxic to humans and animals. Particularly suitable core materials also include those materials known to degrade and/or dissolve in humans and animals. Suitable core materials include beta-tricalcium phosphate, hydroxyapatite, PLGA, and combinations thereof. Beta-tricalcium phosphate cores are particularly suitable, since beta-tricalcium phosphate can be degraded. In other embodiments, the material of the core may be dissolved after the mineral coating is formed. In other embodiments, the material of the core is non-degradable.
The mineral coating includes calcium, phosphate, carbonate and combinations thereof. To prepare the mineral coated microparticles, the core material is incubated in a modified mock body fluid. The modified simulated body fluids include calcium and phosphate, which form a mineral coating on the surface of the core, thereby forming mineral coated particles. Different mineral coating morphologies can be achieved by varying the calcium, phosphate and carbonate content and ratios. Different mineral coating morphologies include, for example, plate-like structures, spherulite-like structures. The high carbonate concentration results in a mineral coating with a plate-like structure. The low carbonate concentration results in a mineral coating with a spherulitic structure. The morphology of the mineral coating also affects the adsorption of the active agent.
Suitable core materials on which the mineral coating is formed include polymers, ceramics, metals, glasses and combinations thereof in particulate form. Suitable particles can be, for example, agarose beads, latex beads, magnetic beads, polymer beads, ceramic beads, metal beads (including magnetic metal beads), glass beads, and combinations thereof. The microparticles include ceramics (e.g., hydroxyapatite, β -tricalcium phosphate (β -TCP, β -TCP), magnetite, neodymium), plastics (e.g., polystyrene, polycaprolactone), hydrogels (e.g., polyethylene glycol; polylactic-co-glycolic acid), and the like, and combinations thereof. Particularly suitable core materials are those which are soluble in the body, for example β -tricalcium phosphate (β -TCP ).
Suitable particle sizes may range from about 1 μm to about 100 μm in diameter. Particle diameters can be measured by methods known to those skilled in the art such as, for example, from microscopic image (including light and electron microscopic image) measurements, by filtration of size-selective substrates, and so forth.
The substrate of the core may, for example, be first coated with a poly (alpha-hydroxy ester) film. Particularly suitable poly (alpha-hydroxy esters) may be, for example, poly (L-lactide), poly (lactide-co-glycolide), poly (epsilon-caprolactone), and combinations thereof. It will be appreciated that when preparing any combination of the above films, the films are typically mixed in a suitable organic solvent known in the art. In addition, differences in molecular weight, crystallization rate, glass transition temperature, viscosity, and the like are also considered and understood in the art to prevent phase separation and lack of uniformity in the final substrate. Phase separation and inhomogeneity can be further avoided by varying the mixing ratio of the films used in the substrate.
After preparing a poly (alpha-hydroxy ester) film on a substrate, the surface of the film coating is hydrolyzed under alkaline conditions to produce a surface having COOH and OH groups. After surface hydrolysis, the substrate is incubated in a simulated body fluid containing a suitable mineral-forming material to form a mineral coating. Suitable mineral-forming materials may be, for example, calcium, phosphate, carbonate and combinations thereof.
Simulated Body Fluids (SBF) for use in the methods of the present disclosure typically comprise about 5mM to about 12.5mM calcium ions, including about 7mM to about 10mM calcium ions, and including about 8.75mM calcium ions; from about 2mM to about 12.5mM phosphate ions, including from about 2.5mM to about 7mM phosphate ions, and including from about 3.5mM to about 5mM phosphate ions; and about 4mM to about 100mM carbonate ion.
In some embodiments, the SBF may comprise about 141mM sodium chloride, about 4mM potassium chloride, about 0.5mM magnesium sulfate, about 1mM magnesium chloride, about 5mM calcium chloride, about 2mM potassium phosphate, and about 4mM sodium bicarbonate, and buffered to a pH of about 6.8.
In some embodiments, the SBF may further comprise about 145mM sodium ion, about 6mM to about 9mM potassium ion, about 1.5mM magnesium ion, about 150mM to about 175mM chloride ion, about 4mM HCO3 -And SO of about 0.5mM4 2-Ions.
The pH of SBF may generally range from about 4 to about 7.5, including from about 5.3 to about 6.8, including from about 5.7 to about 6.2, and including from about 5.8 to about 6.1.
Suitable SBFs may include, for example: about 145mM sodium ion, about 6mM to about 9mM potassium ion, about 5mM to about 12.5mM calcium ion, about 1.5mM magnesium ion, about 150mM to about 175mM chloride ion, about 4.2mM HCO3 -About 2mM to about 5mM PO4 2-Ions and about 0.5mM SO4 2-Ions. The pH of the simulated body fluid can be from about 5.3 to about 7.5, including from about 6 to about 6.8.
In one embodiment, SBF may include, for example: about 145mM sodium ion, about 6mM to about 17mM potassium ion, about 5mM to about 12.5mM calcium ion, about 1.5mM magnesium ion, about 150mM to about 175mM chloride ion, about 4.2mM to about 100mM HCO3 -About 2mM to about 12.5mM phosphate ion and about 0.5mM SO4 -Ions. The pH of the simulated body fluid may be from about 5.3 to about 7.5, including from about 5.3 to about 6.8.
In another embodiment, the SBF comprises: about 145mM sodium ion, about 6mM to about 9mM potassium ion, about 5mM to about 12.5mM calcium ion, about 1.5mM magnesium ion, about 60mMTo about 175mM chloride ion, about 4.2mM to about 100mM HCO3 -About 2mM to about 5mM phosphate ion, about 0.5mM SO4 2-Ionic, and has a pH of about 5.8 to about 6.8, including about 6.2 to about 6.8.
In another embodiment, the SBF comprises: about 145mM sodium ion, about 9mM potassium ion, about 12.5mM calcium ion, about 1.5mM magnesium ion, about 172mM chloride ion, about 4.2mM HCO3 -About 5mM to about 12.5mM phosphate ion, about 0.5mM SO4 2-Ion, about 4mM to about 100mM CO3 2-And a pH of about 5.3 to about 6.0.
In embodiments that include a layered mineral coating, the core is incubated in a modified preparation that mimics body fluids. A layer of mineral coating is formed on the core with a latency of a few minutes to a few days. After the initial layer of mineral coating has formed on the core, the particles of mineral coating can be removed from the modified simulated body fluid and washed. To form a multi-layered mineral coating, the mineral coated particles are incubated in a second, third, fourth, etc. modified mock liquid until the desired number of mineral coatings are obtained. During each incubation period, a new mineral coating will form on the previous layer. These steps are repeated until the desired number of mineral coating layers is obtained.
During mineral formation, an active agent can be included in the modified simulated body fluid to incorporate the active agent into the mineral coating during mineral formation. After each layer of mineral is formed, the mineral-coated particles are incubated in a carrier comprising at least one active agent to adsorb the active agent onto the mineral coating. After incorporating the active agent into and/or adsorbing the active agent to the layer of the mineral coating, another layer of the mineral coating can be formed by incubating the microparticles in another formulation that mimics a body fluid. If desired, the layers of the mineral coating can incorporate an active agent in the mineral, each layer can have an active agent adsorbed onto the mineral layer, the layers of the mineral coating can be formed without incorporating or adsorbing an active agent, and combinations thereof. Mineral coated particles with different levels of mineral coating can be prepared by: a layer of mineral is formed using one modified simulated body fluid formulation and then the mineral coated particles are incubated in another modified simulated body fluid formulation. Thus, the mineral coated particulate can be prepared with multiple layers of mineral coatings, each of which is different. Embodiments are also contemplated that include the same two or more mineral coatings in combination with different one or more mineral coatings.
Specifying the composition of the mineral coating in different layers advantageously allows for a specified release kinetics of the one or more active agents from each layer of the mineral coating.
In embodiments where it is desired to incorporate one or more active agents within the mineral coating, the active agent is included in the SBF. When the mineral is formed, the active agent is incorporated into the mineral coating.
In other embodiments, the magnetic material may be incorporated into the mineral coating. For example, superparamagnetic iron oxide linked to bovine serum albumin may be incorporated into the mineral coating. The attached protein (e.g., bovine serum albumin) can be adsorbed onto the mineral coating to bind the magnetic material to the mineral coating.
In some embodiments, the mineral coating further comprises a dopant. Suitable dopants include halide ions, such as fluoride, chloride, bromide and iodide. The dopant may be added to the other components of the SBF and the substrate is then incubated in the SBF to form the mineral coating.
In one embodiment, the halide ions include fluoride ions. Suitable fluoride ions may be provided by fluoride ion containing agents such as water soluble fluoride salts including, for example, alkali and ammonium fluoride salts.
The fluoride ion containing reagent is typically included in the SBF to provide fluoride ions in an amount up to 100mM, including about 0.001mM to 100mM, including about 0.01mM to about 50mM, including about 0.1mM to about 15mM, and including about 1mM fluoride ions.
It has been found that the inclusion of one or more dopants in the SBF results in the formation of a halogen-doped mineral coating which significantly enhances the delivery efficiency of biomolecules to cells.
In other embodiments, magnetic materials including magnetite, magnetite-doped plastics, and neodymium are used as the particulate core material. The inclusion of magnetic material results in the formation of the MCM, thereby enabling the positioning and/or movement/positioning of the MCM by the application of magnetic forces. The alternative use of magnetic particulate core material allows spatial control of where biomolecule transfer occurs in the culture system, for example when analysing the effect of biomolecules on cells.
The mineral coating may be formed by incubating the substrate with SBF at a temperature of about 37 ℃ for a period of about 3 days to about 10 days.
After preparation of the mineral coating is complete, the mineral coating can be analyzed to determine the morphology and composition of the mineral coating. The composition of the mineral coating can be analyzed by energy dispersive X-ray spectroscopy, fourier transform infrared spectroscopy, X-ray diffraction methods, and combinations thereof. Suitable X-ray diffraction peaks may correspond to the (002), (211), (112) and (202) planes of the hydroxyapatite mineral phase, for example at 26 ° and 31 °, respectively. Particularly suitable X-ray diffraction peaks may correspond to the (002), (112) and (300) planes of carbonate-substituted hydroxyapatite, for example at 26 ° and 31 °, respectively. Other suitable X-ray diffraction peaks may be, for example, at 16 °, 24 ° and 33 °, which correspond to octacalcium phosphate mineral phases. A suitable spectrum obtained by Fourier transform infrared spectroscopy may be, for example, at 450--1At a peak corresponding to the O-P-O bend and at 900--1Peak of (a), which corresponds to asymmetric P-O elongation and hydroxyapatite PO4 3-A group. A particularly suitable spectral peak obtained by Fourier transform infrared spectroscopy may be, for example, at 876cm-1、1427cm-1And 1483cm-1Peak of (a), which corresponds to Carbonate (CO)3 2-) A group. HPO4 2-Can be influenced by adjusting the calcium and phosphate ion concentrations of SBF used to prepare the mineral coating. For exampleHPO may be increased by increasing the calcium and phosphate concentration of SBF4 2-Peak(s). Alternatively, HPO can be reduced by reducing the calcium and phosphate concentration of SBF4 2-Peak(s). Another suitable peak obtained by Fourier transform infrared spectroscopy analysis may be, for example, octacalcium phosphate mineral phase at 1075cm-1The peaks obtained, which can be influenced by adjusting the calcium and phosphate ion concentrations in the simulated body fluids used for the preparation of the mineral coating. For example, 1075cm can be made by increasing the calcium and phosphate ion concentrations in simulated body fluids used to prepare mineral coatings-1The peaks are more distinct. Alternatively, 1075cm can be reduced by reducing the calcium and phosphate ion concentrations in simulated body fluids used to prepare mineral coatings-1The sharpness of the peak is reduced.
Energy dispersive X-ray spectroscopy can also be used to determine the calcium/phosphate ratio of the mineral coating. For example, the calcium/phosphate ratio can be increased by reducing the calcium and phosphate ion concentrations in the SBF. Alternatively, the calcium/phosphate ratio can be reduced by increasing the calcium and phosphate ion concentration in the SBF. Carbonate (CO) can be determined by energy dispersive X-ray spectroscopy analysis of the mineral coating3 2-) Substituted PO4 3-And HPO4 2-Degree of incorporation into mineral coatings. Typically, SBF includes calcium and phosphate ions in a ratio of about 10:1 to about 0.2:1, including about 2.5:1 to about 1: 1.
Furthermore, the morphology of the mineral coating can be analyzed by, for example, scanning electron microscopy. Scanning electron microscopy can be used to visualize the morphology of the resulting mineral coating. The morphology of the resulting mineral coating can be, for example, spherical microstructures, plate-like microstructures and/or network-like microstructures. Suitable average diameters of the spherulites of the spherical microstructure can range, for example, from about 2 μm to about 42 μm. Particularly suitable average diameters of the spherulites of the spherical microstructure may be in the range of, for example, about 2 μm to about 4 μm. In another embodiment, a particularly suitable average diameter of the spherulites of the spherical microstructure may be in a range of, for example, about 2.5 μm to about 4.5 μm. In another embodiment, a particularly suitable average diameter of the spherulites of the spherical microstructure may be in a range of, for example, about 16 μm to about 42 μm.
The mineral coated particles can be stored for later use, washed and used immediately for the adsorption step, or used immediately for the adsorption step without washing.
To adsorb the active agent onto the mineral coated particles, the mineral coated particles are contacted with a solution containing the active agent. As used herein, "active agent" refers to a bioactive material. The active agent may be contacted with the mineral coated particles using any method known in the art. For example, a solution of the active agent can be pipetted, poured or sprayed onto the mineral coated particles. Alternatively, the mineral coated particles may be immersed in a solution containing the active agent. The active agent is adsorbed onto the mineral coating by electrostatic interaction between the active agent and the mineral coating of the mineral coated particulate. Suitable active agents include biomolecules. Particularly suitable active agents include interleukin-1 (IL-1; IL1F1) antagonists; and an IL-1F2 antagonist; an IL-1F3 antagonist; an IL-1F4 antagonist; an IL-1F5 antagonist; an IL-1F6 antagonist; an IL-1F7 antagonist; an IL-1F8 antagonist; an IL-1F9 antagonist; an IL-1F10 antagonist; an IL-1F11 antagonist; (iii) acalep; rituximab; (ii) toclizumab; anakinra; adalimumab; etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. A particularly suitable IL-1 antagonist is an IL-1 receptor antagonist (IL-Ra), which is a natural antagonist of proinflammatory IL-1. Specific suitable IL-Ra include anakinra (e.g., anakinra
Adsorption of the active agent by the mineral coated particles can be specified by varying the mineral ingredients (e.g., high carbonate and low carbonate microspheres), by varying the amount of mineral coated particles incubated with the active agent, by varying the concentration of the active agent in the incubation solution, and combinations thereof.
As the mineral coating degrades, the active agent adsorbed onto the mineral coating of the mineral coated particles is released. Mineral degradation can be controlled so that the mineral coating can degrade quickly or slowly. The dissolution rate of the mineral coating can be controlled by varying the composition of the mineral coating. For example, mineral coatings with higher degrees of carbonate substitution degrade faster. Mineral coatings with lower carbonate substitution degraded more slowly. Doping with dopants such as fluoride ions may also alter dissolution kinetics. The change in the composition of the mineral coating can be achieved by changing the ion concentration in the modified simulated body fluid during the formation of the coating. The modified simulated body fluid with a higher carbonate concentration (e.g., 100mM carbonate) resulted in faster degradation of the coating than the coating formed in the modified simulated body fluid with a physiological carbonate concentration (4.2mM carbonate).
To incorporate the active agent into the mineral coated particles, the active agent is included in the simulated body fluid during the mineral coating process. Specific suitable active agents include interleukin-1 (IL-1; IL1F1) antagonists; and an IL-1F2 antagonist; an IL-1F3 antagonist; an IL-1F4 antagonist; an IL-1F5 antagonist; an IL-1F6 antagonist; an IL-1F7 antagonist; an IL-1F8 antagonist; an IL-1F9 antagonist; an IL-1F10 antagonist; IL-1F11 Albapup; rituximab; (ii) toclizumab; anakinra; adalimumab. Etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. Particularly suitable IL-1 antagonists are IL-1 receptor antagonists (IL-Ra), which are natural antagonists of proinflammatory IL-1. Specific suitable IL-Ra include anakinra (e.g., anakinra
To adsorb the active agent on the different layers of the mineral coated particles, after each layer is formed, the mineral coated particles are incubated in a solution containing the active agent. Some layers may not have an active agent adsorbed on the surface. Particularly suitable active agentsIncluding interleukin-1 (IL-1; IL1F1) antagonists; and an IL-1F2 antagonist; an IL-1F3 antagonist; an IL-1F4 antagonist; an IL-1F5 antagonist; an IL-1F6 antagonist; an IL-1F7 antagonist; an IL-1F8 antagonist; an IL-1F9 antagonist; an IL-1F10 antagonist; IL-1F11 Albapup; rituximab; (ii) toclizumab; anakinra; adalimumab. Etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. Particularly suitable IL-1 antagonists are IL-1 receptor antagonists (IL-Ra), which are natural antagonists of proinflammatory IL-1. Specific suitable IL-Ra include anakinra (e.g., anakinra) Is a recombinant form of IL-Ra approved by the U.S. Food and Drug Administration (FDA) for the treatment of systemic chronic inflammation.
The formulations of the present invention can then be prepared by adding the carrier to the mineral coated particles with the active agent adsorbed onto the mineral coating. In one embodiment, a carrier comprising an active agent can be added to a mineral-coated particulate having an active agent adsorbed onto the mineral coating to produce a formulation comprising a bound active agent (active agent adsorbed onto the mineral-coated particulate) and an unbound active agent. In another embodiment, a carrier that does not contain an active agent can be added to mineral coated microparticles with an active agent adsorbed to the mineral to produce a formulation containing a bound active agent.
In particularly suitable formulation embodiments, the formulation includes both conjugated and unconjugated active agents. Without being bound by theory, it is believed that a formulation comprising injecting mineral coated microparticles with bound and unbound active agent allows the unbound active agent to provide an immediate effect, while the bound active agent is sequestered by its adsorption onto the mineral coated microparticles and provides a sustained action as the mineral coating degrades and releases the active agent.
In one embodiment, the carrier is a pharmaceutically acceptable carrier. As understood by those skilled in the art, a pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients, must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Suitable pharmaceutically acceptable carrier solutions include water, saline, isotonic saline, phosphate buffered saline, ringer's lactate, and the like. The compositions of the invention can be administered to animals, preferably to mammals, in particular to humans, as therapeutic agents per se, as a mixture with one another or in the form of pharmaceutical preparations, and as active ingredient comprise an effective dose of the active agent, together with customary pharmaceutically harmless excipients and additives.
Formulations for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusions or in multi-dose containers with and without added preservatives. The formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the mineral coated particles with active agent may be in powder form, e.g. obtained by lyophilization from solution, for dissolution in a suitable vehicle, e.g. sterile, pyrogen-free water, prior to use.
In one aspect, the present disclosure is directed to a mineral-coated particulate comprising at least one active agent incorporated into a mineral coating and at least one active agent adsorbed onto the mineral coating.
As disclosed herein, to incorporate an active agent within the mineral coated particles, the active agent is included in the simulated body fluid during the mineral coating process. Specific suitable active agents include those described herein.
As described herein, the active agent can be adsorbed onto the mineral coating. The active agent may also be incorporated into the mineral of the mineral coated particulate, as described herein. The active agent may further adsorb to the mineral coating and be incorporated into the mineral of the mineral coated particulate, as described herein. As also described herein, different active agents may be adsorbed to or incorporated into the mineral coating.
In another aspect, the present disclosure relates to methods for immediate and sustained delivery of active agents. The method comprises providing to an individual in need thereof a formulation comprising a carrier, wherein the carrier comprises at least a first active agent; and mineral-coated particles comprising at least one second active agent adsorbed onto the mineral coating.
In one embodiment, the active agent adsorbed onto the mineral coating is the same as the active agent in the carrier. In another embodiment, the active agent adsorbed onto the mineral coating is different from the active agent in the carrier. In another aspect, at least two different active agents are adsorbed to the mineral coating.
Suitable methods of administration of the formulations of the invention are by the parenteral (e.g., IV, IM, SC or IP) route, and the formulations generally administered include an effective amount of the product together with acceptable diluents, carriers and/or adjuvants. Standard diluents, such as human serum albumin, and standard carriers, such as saline, are contemplated for use in the pharmaceutical compositions of the present invention.
The sustained delivery of the active agent can be determined to obtain an active agent release value that mimics the established therapeutic level of the active agent. The mass of mineral coated particles (with active adsorbed) required to deliver the desired concentration of active over a period of time can be pre-calculated. For example, by obtaining an active agent release value from a mineral coated microparticle, a single bolus of the active agent can be delivered continuously over a desired period of time to provide a desired therapeutic effect. The mass of mineral coated microparticles required to deliver the active agent can then be calculated to provide the desired period of therapeutic effect. A local and sustained delivery platform provides the benefit of the active agent remaining at therapeutic levels at the site of injury consistently without multiple injections.
It is contemplated that the effective dosage will vary significantly depending on the active agent or agents used and the particular disease, disorder or condition being treated. Due to the rapid and sustained delivery of the active agent contained in the formulations of the present disclosure, it is contemplated that the appropriate dose is less than the effective dose of the active agent delivered by bolus injection (bolus injection). As described herein, mineral coated microparticles can be prepared to deliver an effective amount of active agent over the course of several days. Thus, administration of the formulations of the present application provides bolus administration of unbound active agent with a rapid effect and sustained release of the active agent during degradation of the mineral coating of the mineral coated microparticles such that the active agent is continuously released to maintain the effect for a period of hours to days as needed.
The formulations of the invention can be administered to a subject in need thereof. As used herein, "subject" (also interchangeably referred to as "individual" and "patient") refers to an animal including both human and non-human animals. Thus, the compositions, devices and methods disclosed herein are useful for human and veterinary applications, particularly human and veterinary medical applications. Suitable subjects include warm-blooded mammalian hosts, including humans, companion animals (e.g., dogs, cats), cows, horses, mice, rats, rabbits, primates, and pigs, preferably human patients.
As used herein, a "subject in need thereof" (also used herein interchangeably with "patient in need thereof") refers to a subject susceptible to or at risk for a particular disease, disorder or condition. The methods disclosed herein may be used on a subset of subjects predisposed to or at increased risk of developing inflammatory diseases and conditions. Some embodiments of the methods described herein relate to a particular subset or subclass of subjects identified (i.e., a subset or subclass of subjects "in need of" assistance in addressing one or more particular diseases described herein), and thus not all subjects for a certain disease, disorder or condition described herein will fall within that subset or subclass of subjects.
In another aspect, the invention relates to a method of treating an inflammatory disease in a subject in need thereof. The method comprises administering a formulation to a subject, wherein the formulation comprises a carrier comprising an active agent and a mineral-coated particulate, wherein the mineral-coated particulate comprises an active agent.
In some embodiments, the method relates to systemic treatment of rheumatoid arthritis. In some embodiments, the method relates to the topical treatment of osteoarthritis.
Inflammatory diseases include arthritis, particularly rheumatoid arthritis and osteoarthritis. Other suitable inflammatory diseases include interleukin-1 related diseases such as
The formulation may be administered by injection. For osteoarthritis, the formulation may be injected via the synovium.
In one embodiment, the active agent adsorbed onto the mineral coating is the same as the active agent in the carrier. In another embodiment, the active agent adsorbed onto the mineral coating is different from the active agent in the carrier. In another aspect, at least two different active agents are adsorbed to the mineral coating.
Suitable active agents are described herein. Specific suitable active agents include interleukin-1 (IL-1; IL1F1) antagonists; and an IL-1F2 antagonist; an IL-1F3 antagonist; an IL-1F4 antagonist; an IL-1F5 antagonist; an IL-1F6 antagonist; an IL-1F7 antagonist; an IL-1F8 antagonist; an IL-1F9 antagonist; an IL-1F10 antagonist; IL-1F11 Albapup; rituximab; (ii) toclizumab; anakinra; adalimumab. Etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. Particularly suitable IL-1 antagonists are IL-1 receptor antagonists (IL-Ra), which are natural antagonists of proinflammatory IL-1. Specific suitable IL-Ra include anakinra (e.g., anakinra) It is a recombinant form of IL-Ra approved by the U.S. Food and Drug Administration (FDA) for the treatment of systemic chronic inflammation.
A suitable method of administering the formulations of the invention is by the parenteral (e.g., IV, IM, SC, or IP) route described herein.
In another aspect, the present invention relates to a method of treating post-operative inflammation in a subject in need thereof. The method comprises administering a formulation to a subject, wherein the formulation comprises a carrier comprising an active agent and a mineral-coated particulate, wherein the mineral-coated particulate comprises the active agent.
Suitable active agents are described herein. Specific suitable active agents include interleukin-1 (IL-1; IL1F1) antagonists; and an IL-1F2 antagonist; an IL-1F3 antagonist; an IL-1F4 antagonist; an IL-1F5 antagonist; an IL-1F6 antagonist; an IL-1F7 antagonist; an IL-1F8 antagonist; an IL-1F9 antagonist; an IL-1F10 antagonist; IL-1F11 Albapup; rituximab; (ii) toclizumab; anakinra; adalimumab. Etanercept; infliximab; (ii) semuzumab; golimumab; and combinations thereof. Particularly suitable IL-1 antagonists are IL-1 receptor antagonists (IL-Ra), which are natural antagonists of proinflammatory IL-1. Specific suitable IL-Ra include anakinra (e.g., anakinra
A suitable method of administering the formulations of the invention is by the parenteral (e.g., IV, IM, SC, or IP) route described herein.
Examples
- 上一篇：一种医用注射器针头装配设备
- 下一篇：用于治疗血液病的化合物和组合物