Slow-release, prolonged-action subcutaneous pharmaceutical formulation for the release of vitamin d

Abstract

The present invention is directed to the pharmaceutical sector and describes methods for administering vitamin D parenterally using resorbable polymers in the form of in situ forming implants; compression-formed implants, extrusion-formed implants, and liquid preparations. For long-acting vitamin D delivery system formulations, 0.5% to 99% by weight of resorbable polymers and 0.5% to 60% of organic solvents are used. Additionally, plasticisers in the concentration range of 0.1% to 50% may be used to assist in the extrusion process. The vitamin D dosage ranges from 2,000 to 2,000,000 IU, delivering 400 to 2,000 IU daily, without an initial peak release, thus reducing the risk of hypercalciuria.

Description

[0001] Subcutaneous pharmaceutical formulation with slow and prolonged release of vitamin D.

[0002] Field of invention

[0003]

[0001] This patent application is directed to the pharmaceutical sector and describes an innovative method for administering vitamin D parenterally, subcutaneously or intramuscularly using resorbable polymers, solvents and plasticizers to increase levels in patients with serum 25-hydroxyvitamin D deficiency or insufficiency. This method not only improves therapeutic adherence but also offers a controlled and safe release of long-acting vitamin D, significantly reducing the risks associated with megadose administration, such as hypercalciuria.

[0004] Fundamentals of the invention and state of the art

[0005]

[0002] Vitamin D is a fat-soluble vitamin that can be obtained through diet, as well as being synthesized in the skin from 7-dehydrocholesterol (pro-vitamin D3) and ultraviolet B radiation (UVB, 290-329 nm), and is also considered a seco-steroid prohormone.

[0006]

[0003] There are two main forms of vitamin D: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is found in plant sources, while vitamin D3 is synthesized by human skin when exposed to sunlight and can also be obtained from certain foods of animal origin. Few foods naturally contain vitamin D, so dermal synthesis after sun exposure remains the primary route of obtaining it, accounting for 90% of its supply in humans.

[0007]

[0004] Both vitamin D3 and D2 are biologically inactive and need to be converted in the body into their active forms. First, they undergo 25-hydroxylation in the liver by the enzyme CYP2R1 into 25(OH)D (Calcidiol), the main circulating form of vitamin D, with a half-life of 2 to 3 weeks. This form is then converted in the kidneys through a 1-alpha-hydroxylation reaction by the enzyme CYP27B1 into its more active form, 1,25(OH)D (Calcitriol), with a half-life of 4 to 6 hours, which binds to the vitamin D receptor (VDR) to enable its various physiological functions.

[0008]

[0005] Vitamin D is essential for human health, playing a crucial role in regulating calcium and phosphorus in the body, as well as being fundamental for bone health, since it facilitates the absorption of calcium in the intestine.

[0009]

[0006] In addition, vitamin D has immunomodulatory, anti-inflammatory and antioxidant functions, contributing to the prevention of several chronic diseases, such as osteoporosis, diabetes and cardiovascular diseases.

[0010]

[0007] Currently, there is no standard definition of ideal vitamin D status. Laboratory detection of vitamin D deficiency is based on measuring serum concentrations of 25-hydroxyvitamin D (25(OH)D), the vitamin D metabolite that best reflects the overall supply from all different sources of vitamin D, and this is the accepted parameter for vitamin D status.

[0011]

[0008] There is broad consensus that serum 25(OH)D concentrations below 25 to 30 nmol / L (10 to 12 ng / mL) indicate vitamin D deficiency and should be prevented and treated by vitamin D intake. For serum 25(OH)D concentrations from 25-30 nmol / L (10-12 ng / mL) up to 75 nmol / L (30 ng / mL), there is controversy regarding the sufficiency threshold, with the main scientific debate being whether concentrations > 50 nmol / L (20 ng / mL) or > 75 nmol / L (30 ng / mL) should be the target 25(OH)D level for vitamin D sufficiency.

[0012]

[0009] Vitamin D deficiency is a significant global problem, affecting millions of people due to low sun exposure, inadequate diets, and other factors. Vitamin D deficiency, also called "hypovitaminosis D" or "subclinical vitamin D deficiency," is prevalent in many populations around the world, especially in regions with low incidence of sun exposure. Studies indicate that vitamin D deficiency is associated with an increased risk of bone disease, muscle weakness, and compromised immune system.

[0013]

[0010] Oral administration is the most common method of vitamin D supplementation, but patient adherence can be compromised when the regimen involves daily or weekly oral doses, and also due to gastrointestinal effects or difficulties in swallowing capsules.

[0014]

[0011] In a prospective study that followed bone changes in patients undergoing biliopancreatic diversion (BPD), one third of patients who should have been taking oral vitamin D supplements did not follow the treatment correctly and admitted to rarely taking the supplements or interrupting treatment for several months (MARCEAU, P. et al. Does bone change after biliopancreatic diversion? Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract, v. 6, n. 5, p. 690-698, 2002).

[0015]

[0012] Alternatively, semi-annual or annual supplementation via injections significantly improves adherence to treatment, providing a sustained release of the nutrient into the body. Megadose administration has proven effective in correcting vitamin D deficiency. Studies have shown that high doses administered every six months or annually are safe and well tolerated by most patients.

[0016]

[0013] Referring to the state of the art regarding patent registrations, documents number W020081 16809A1 and ES2592155T3 can be cited, which claim pharmaceutical compositions comprising a bisphosphonate and vitamin D and bisphosphonate and vitamin D formulations suitable for intermittent intramuscular and subcutaneous administration, respectively.

[0017]

[0014] The first registration number W020081 16809A1 claims parenteral pharmaceutical compositions comprising vitamin D, or a bisphosphonate and vitamin D, for the treatment or prevention of diseases of abnormal bone remodeling and / or vitamin D deficiency. Vitamin D is provided in doses of 100,000 IU, 200,000 IU, 300,000 or 600,000 IU. Such a formulation may be used once every 6 months or annually, or for even less frequent dosing, including a single administration. The parenteral composition is preferably administered by infusion.

[0018]

[0015] The second registration ES2592155T3 describes a composition for pharmaceutical use containing a substance from the bisphosphonate class and vitamin D, in which all components are dissolved in a lipid and phospholipid emulsion in water at a concentration of 5% or 0.5% w / v in a volume suitable for intramuscular or subcutaneous administration. The composition is characterized by the fact that the concentration of vitamin D is not less than 600 IU / ml and preferably between 600 IU / ml and 720,000 IU / ml. The vitamin D in question is vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), calcifediol, alfacalcidol or calcitriol or a combination thereof, or a metabolite, precursor, derivative or analogue thereof, preferably vitamin D3 (cholecalciferol). The components (vitamin D and bisphosphonate) are contained separately in syringe vials and are combined before injection.

[0019]

[0016] Other related prior works, such as articles, are cited below:

[0017] “Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young people with vitamin D deficiency: a prospective intervention study” (The Journal of Clinical Endocrinology & Metabolism, Volume 95, Issue 10, October 1, 2010, pages 4771-4777, https: / / doi.org / 10.1210 / jc.2010-0502).

[0020]

[0018] “Safety and efficacy of megadose vitamin D: a systematic review” (ESPEN Clinical Nutrition, Volume 46, pages 115-120, December 1, 2021, https: / / doi.org / 10.1016 / j.clnesp.2021.09.010).

[0021]

[0019] “A randomized controlled trial on the safety and efficacy of single intramuscular dose versus escalating oral dose of 600,000 IU of vitamin D in the treatment of nutritional rickets” (Journal of Tropical Pediatrics, Volume 60, Issue 3, pages 203-210, June 1, 2014, https: / / doi.org / 10.1093 / tropej / fmt105).

[0022]

[0020] The problem related to the issues mentioned above lies in the risk associated with administering megadoses of vitamin D, known as hypercalciuria, especially in the first few days after administration in patients who do not consume sufficient amounts of water. Hypercalciuria can lead to renal complications if not properly controlled. Hypervitaminosis D results in hypercalcemia due to increased intestinal absorption of calcium and bone resorption, which, depending on the duration, can cause kidney damage.

[0023]

[0021] Vitamin D supplements are increasingly available in both industrialized and developing countries. However, the lack of adequate guidance for therapeutic supplementation or public education has likely led to complications at the other end of the spectrum of vitamin D metabolism abnormalities, namely vitamin D toxicity or hypervitaminosis D. In a retrospective analysis of data from the National Poison Data System (NPDS), toxic exposure to vitamin D increased from an average of 196 cases per year between 2000 and 2005 to an average of 4,535 exposures per year between 2005 and 2011.

[0024]

[0022] When vitamin D intoxication occurs, metabolites (mainly 1,25-vitamin D) appear at elevated levels, overloading the capacity of vitamin D transport proteins and exacerbating the liver's ability to metabolize and excrete the vitamin. Acute vitamin D intoxication results in hypercalcemia and hyperphosphatemia, which can lead to the development of nephrocalcinosis, hypercalciuria, and hypertension of renal origin. With hypercalcemia intoxication, the central nervous system may exhibit alterations such as seizures, tetany, neuromuscular hyperexcitability, paresthesia, and coma.

[0025]

[0023] In the mid- to late period of absorption of injected vitamin D into the body, the rate of diffusion from the injection site into the systemic circulation decreases as the concentration of vitamin D decreases at the injection site. This results in a slower release in the final period.

[0026]

[0024] A daily dose of 2,000 IU of vitamin D supplement is a reasonable approach to prevent and treat vitamin D deficiency. Conventional doses of vitamin D, such as 600 to 800 IU (15 to 20 pg), may not be sufficient for many individuals to reach the conservative target concentration of at least 50 nmol / L (20 ng / mL) when considering the wide interindividual dose range and when taking into account multiple clinical factors such as obesity, malabsorption syndromes (which may not always be diagnosed yet), or medications that impair vitamin D metabolism (e.g., antiepileptic drugs), requiring higher doses of vitamin D.

[0027]

[0025] The present invention provides a pharmaceutical formulation for subcutaneous use that promotes the release of vitamin D over a prolonged period. This formulation was specifically designed to avoid the initial increase in serum concentration commonly associated with other methods of administration. By maintaining a constant and controlled release of vitamin D, the formulation ensures efficient and consistent serum levels, optimizing therapeutic outcomes for patients with vitamin D deficiency or insufficiency. A key feature of this invention is its ability to mitigate the risk of hypercalciuria, since the controlled release mechanism of the formulation avoids sudden spikes in serum calcium levels.

[0028] Figure Description

[0029]

[0026] Figure 1 illustrates the process of vitamin D metabolism in the body.

[0030] Detailed description of the invention

[0031]

[0027] The term vitamin D used herein (as per Figure 1) refers to analogues, precursors, derivatives or metabolites of vitamin D that can be used in pharmaceutical compositions, such as Colecalciferol (vitamin D3), Ergocalciferol (vitamin D2), Calcifediol (25-hydroxyvitamin D3), Calcitriol (1,25-dihydroxyvitamin D3), Alfacalcidol (1α-hydroxyvitamin D3), Doxercalciferol (1α-hydroxyvitamin D2), Paricalcitol (19-nor-1,25-dihydroxyvitamin D2), Calcipotriol (calcipotriene), Tacalcitol, 22-oxacalcitriol, Falecalcitriol, Maxacalcitol, Seocalcitol and Lexacalcitol. In a preferred embodiment of the invention, vitamin D is provided as Colecalciferol.

[0032]

[0028] In the present application, 1 IU (International Unit) of vitamin D3 is equivalent to 0.025 micrograms of cholecalciferol (vitamin D3).

[0029] The term “pharmaceutical formulation” for subcutaneous or intramuscular use used herein refers to formulations that can be adapted to achieve specific release profiles, stability requirements and patient adherence, making them suitable for the administration of vitamin D and its derivatives. In a preferred embodiment of the invention, the pharmaceutical formulations may be biodegradable implants, liquid injections or in situ forming implants.

[0033]

[0030] “Implant” refers to a pharmaceutical form recognized in official collections of standards for medicines and pharmaceutical substances. They are solid, sterile preparations designed for parenteral implantation, which release the active substance over a prolonged period. Extended-release implants consist of a matrix of medicinal substance and polymeric excipient that may or may not have an outer rate-controlling membrane. The polymeric excipient must be biocompatible but may or may not be bioabsorbable. The medicinal substance may or may not be pre-dissolved in a biocompatible aprotic polar solvent. The implants must be sterile and generally have a cylindrical shape, although other shapes are used. In a preferred embodiment of the invention, the implants described herein are biodegradable, do not have an outer rate-controlling membrane, and the medicinal substance is pre-dissolved in an aprotic solvent.The preferred shape is cylindrical, and the production method can be either extrusion or compression.

[0034]

[0031] “In situ forming implants” are liquid formulations that generate solid or semi-solid deposits after administration to specific therapeutic targets. This drug delivery strategy allows for localized delivery and sustained release of the drug over periods of days to months. They typically consist of polymers in organic solvents, and after injection, the solvents migrate out of the site, leaving a gelled mass. The preparations can be injected as is, after reconstitution, from “in situ” formation, or from chemically initiated catalysis resulting in the final form. In a preferred embodiment of the invention, the in situ forming implants generate a solid deposit, and the preparations containing the drug and polymers are mixed before injection.

[0035]

[0032] The term “Luer-Lock” refers to a connection mechanism used in medical devices, especially syringes and needles, to ensure a secure and leak-proof connection between different components. This connection system is designed to facilitate the quick and safe assembly and disassembly of syringes and other fluid delivery devices, minimizing the risk of accidental leaks or disconnections.

[0036]

[0033] For the formulation of long-acting pharmaceutical compositions intended for subcutaneous use in the administration of vitamin D, biocompatible and bioabsorbable polymers are used, such as polylactic acid (PLA) including poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(DL-lactic acid) (PDLLA); polyglycolic acid (PGA); poly(lactic acid-co-glycolic acid) (PLGA) and their different proportions such as PLGA 50:50, PLGA 75:25; polycaprolactone (PCL); polyanhydrides; polyorthoesters; polyhydroxyalkanoates (PHAs), such as polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), polyhydroxybutyrate-co-hydroxyvalerate (PHBV); polycarbonates such as trimethylene carbonate (TMC), polyethylene carbonate (PEC); polydioxanone (PDO); poly(trimethylene carbonate) (PTMC); poly(ethylene glycol) (PEG) alone or combined with other biodegradable polymers (PEGylated polymers); poly(ethylene oxide) (PEO); poly(gamma-glutamic acid) (gamma-PGA);poly([3-malic] acid (PMA); polycaprolactone (PCL); chitosan and its derivatives; alginate; collagen; gelatin; hyaluronic acid; fibrin; silk fibroin; poly(amino acids); polyphosphazenes; starch-based polymers; dextran; cellulose derivatives such as carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), methylcellulose (MC); polysaccharides such as xanthan gum, pullulan, agarose; poly(ether ester) copolymers such as poly(ethylene glycol)-poly(lactic acid) (PEG-PLA), poly(ethylene glycol)-poly(caprolactone) (PEG-PCL); poly(ether ester amide copolymers); biodegradable polyurethanes; poly(sebacic anhydride) (PSA); poly(glycerol sebacate) (PGS); poly(ethylene glycol)-poly(s-caprolactone) (PEG-PCL); poly(propylene fumarate) (PPF);Poly(acrylic acid) (PAA), Polyvinylpyrrolidone (PVP). In a preferred embodiment of the invention, poly(lactic-co-glycolic acid) (PLGA), poly L-lactic acid (PLLA), polycaprolactone (PCL), polyglycolic acid (PGA), polyvinylpyrrolidone (PVP) are used, as well as their combinations and racemic mixtures (D and L conformations) of monomers and those with different proportions between monomers.

[0037]

[0034] The concentration of biocompatible and bioabsorbable polymers in the formulation can vary from 0.5% to 99% by weight. In a preferred embodiment of the invention, considering bioabsorbable implants, the polymer concentration range is from 30% to 70%, and considering in situ implants, the polymer concentration range is from 40% to 60%, and for liquid injectable preparations, from 0.5% to 5%.

[0038]

[0035] A polar aprotic solvent is used to dissolve vitamin D and ensure its incorporation into the polymer matrix, as well as to stabilize vitamin D during manufacturing and storage. The polar aprotic solvent is used to dissolve and suspend the polymer matrix, ensuring its homogeneity, dispersibility, and stabilization during storage. The organic solvents used are biocompatible with the human body to avoid toxicity and prevent adverse reactions.The solvents used may include triacetin (glyceryl triacetate), benzyl benzoate, benzyl alcohol, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, ethanol, propylene glycol, glycerol, polyethylene glycol (PEG 300, PEG 400), diethylene glycol monoethyl ether (transcutol), polysorbates (polysorbate 20 and polysorbate 80), propylene carbonate, caprylic / capric triglyceride (MCT), isopropyl myristate, triethyl citrate, acetone, ethyl acetate, methyl acetate, ethyl lactate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide (DMSO), dimethyl isosorbide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid and 1- dodecylazacycloheptan-2-one, as well as mixtures and combinations thereof. In a preferred embodiment of the invention, dimethyl sulfoxide and N-methyl-2-pyrrolidone are used.

[0039]

[0036] The concentration of the polar aprotic solvent or a combination of two or more solvents will depend on the specific requirements of the formulation, including the safety profile, solubility, stability and intended drug release rate in the formulation, and may vary from 0.5 to 60% by weight.

[0040]

[0037] For implants manufactured by the extrusion process, some additives and excipients can be used. These can be called plasticizers. The function of the plasticizer is to reduce the glass transition temperature (Tg) of the polymer, or the polymer mixture, to aid in processing, either by reducing the screw rotation torque or by reducing the maximum temperature required for material melting.

[0041]

[0038] The plasticizer can be used in solid or liquid form. Plasticizers for the intended use are: stearic acid, magnesium stearate, glyceryl behenate, citrate ester, triacetin, glycerol, polyvinylpyrrolidone, mannitol, sorbitol lactate, ethyl lactate, butyl lactate, lactose, low molecular weight polyols such as propylene glycol, low molecular weight polyethylene glycol. The range of use of the plasticizer can be between 0.1 and 50% of the formulation by weight.

[0039] The vitamin D concentration varies between 2,000 IU and 2,000,000 IU of the formulation by weight. Because it is able to stabilize the dosage through the proposed invention, the vitamin D dosage for this system provides biodegradable implants and in situ formers of 50,000 IU to 2,000,000 IU, reaching 1.25 mg to 50 mg of cholecalciferol per formulation, with an initial burst release limit.

[0042]

[0040] Vitamin D is released from the pharmaceutical composition in an amount sufficient to provide the patient with their daily vitamin D requirement, ranging from 400 IU to 2,000 IU daily and allowing for vitamin D release from 60 to 1,000 days depending on the intended dosage interval of the composition.

[0043]

[0041] The vitamin D release rate from the pharmaceutical composition is evaluated through an internally developed and validated dissolution procedure. In summary, the procedure uses a pharmacopoeiically described dissolution apparatus and a dissolution medium that simulates the pH and osmolarity of subcutaneous tissue. The amount of drug released at different times is determined using an internally developed and validated chromatographic method, and cumulative dissolution rates are calculated from the change in drug concentration in the dissolution medium.

[0044]

[0042] For the production of the pharmaceutical composition described herein, vitamin D or its derivative is dissolved in the selected biocompatible solvent and then mixed into a polymer mixture, such as PLGA and PCL. The mixture can be compressed to produce implants using a compression molding machine, or the implants can be molded using an extrusion machine. When the extrusion process is selected, the extruded filament is cut into individual implants. A drying step under controlled conditions may be necessary to evaporate the solvent. The implants are then packaged in suitable biocompatible packaging to maintain stability until use. Alternatively, to produce in situ forming implants, the vitamin D or its derivative dissolved in the solvent is bottled separately from the polymer mixture. In this process, the polymers are also dissolved in a biocompatible polar solvent.The solutions are bottled separately and mixed immediately before use using a luer-lock system or other mixing system.

[0045]

[0043] The invention is demonstrated by means of the following non-limiting examples:

[0046]

[0044] Example 1: In situ implant containing 600,000 IU of cholecalciferol (vitamin D3).

[0047] Table 1

[0048]

[0045] For the preparation of an in situ-formed implant of 600,000 IU of cholecalciferol (vitamin D3), the polymer suspension may contain 170 mg (42.5%) of polycaprolactone (PCL) polymer and 215 mg (53.75%) of dimethyl sulfoxide (DMSO) solvent for the administration of 15 mg (3.75%) of cholecalciferol (vitamin D3). The polymer suspension and cholecalciferol (vitamin D3) are stored separately and mixed using a luer-lock system immediately before subcutaneous application. This pharmaceutical composition was formulated to release a daily amount of 50 mcg of cholecalciferol (vitamin D3).

[0049]

[0046] Example 2: In situ implant containing 500,000 IU of cholecalciferol (vitamin D3).

[0050] Table 2

[0051]

[0047] For the preparation of an in situ-formed implant of 500,000 IU of cholecalciferol (vitamin D3), the polymer suspension may contain 160 mg (48.12%) of poly(lactic-co-glycolic acid) (PLGA) polymer and 160 mg (48.12%) of N-methyl-2-pyrrolidone (NMP) solvent for the administration of 12.5 mg (3.76%) of cholecalciferol (vitamin D3). The polymer suspension and cholecalciferol (vitamin D3) are stored separately and mixed using a luer-lock system immediately before subcutaneous application. This pharmaceutical composition was formulated to release a daily amount of 45 mcg of cholecalciferol.

[0052]

[0048] Example 3: Bioabsorbable implant containing 300,000 IU of cholecalciferol (vitamin D3). Table 3

[0053]

[0049] For the preparation of a bioabsorbable implant of 300,000 IU of cholecalciferol (vitamin D3), the polymeric composition may contain 2.5 mg (4%) of polyvinylpyrrolidone (PVP) polymer, 22.5 mg (36%) of polylactic acid (PLA) polymer and 30 mg (48%) of magnesium stearate plasticizer mixed with 7.5 mg (12%) of cholecalciferol (vitamin D3). The implant is manufactured by mixing the vitamin D with the polymers and plasticizer in their dry forms in a suitable container, and the mixture is homogenized. The mixture is added to a punch die and mechanical force is applied, generating compression of the particles. This pharmaceutical composition was formulated to release a daily amount of 25 mcg of cholecalciferol.

[0054]

[0050] Example 4: Bioabsorbable implant containing 2,000,000 IU of cholecalciferol (vitamin D3).

[0055] Table 4

[0051] For the preparation of a bioabsorbable implant of 2,000,000 IU of cholecalciferol (vitamin D3), the polymeric composition may contain 100 mg (50%) of poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 50 mg (25%) of polycaprolactone (PCL) polymer mixed with 50 mg (25%) of cholecalciferol (vitamin D3). The mixture is placed in the extruder feeder and forced into the extrusion cylinder by a screw feeder. The mixture is then heated, cut, mixed, and conveyed through the twin screws of the extrusion cylinder and released at the orifice. The released mass is then cooled to room temperature on a conveyor belt and cut to the established dimensions. This pharmaceutical composition was formulated to release a daily amount of 50 mcg of cholecalciferol.

[0056]

[0052] Example 5: Bioabsorbable implant containing 1,200,000 IU of cholecalciferol (vitamin D3).

[0057] Table 5

[0058]

[0053] For the preparation of a bioabsorbable implant of 1,200,000 IU of cholecalciferol (vitamin D3), the polymeric composition may contain 87.6 mg (73%) of poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 2.4 mg (2%) of mannitol plasticizer mixed with 30 mg (25%) of cholecalciferol (vitamin D3). After mixing, the compounds are ground so that the largest granule size does not exceed 2 mm. The ground mixture is placed in the feeder of an extruder and forced into the extrusion cylinder by a screw feeder. The mixture is then heated, cut, mixed, and conveyed through the twin screws of the extrusion cylinder and released into the orifice. The released mass is then cooled to room temperature on a conveyor belt and cut to the established dimensions. This pharmaceutical composition was formulated to deliver a daily dose of 25 mcg of cholecalciferol.

[0059]

[0054] Example 6: Injectable preparation containing 600,000 IU of cholecalciferol (vitamin D3).

[0060] Table 6

[0061]

[0055] For the injectable preparation of 600,000 IU of Cholecalciferol (vitamin D3), the polymeric composition may contain 5 mg (0.5%) of Poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 10 mg (1.0%) of NMP solvent mixed with 15 mg (1.5%) of Cholecalciferol (vitamin D3) and 970 mg of sunflower oil per ampoule. The PLGA should be dissolved in the NMP solvent by heating to 50°C. eC and subsequently add sunflower oil to the mixture. Completely dissolve the Colecalciferol in the NMP, PLGA and sunflower oil mixture and package in ampoules. This formulation was developed to slow the diffusion rate of Colecalciferol in the tissue, delaying its release.

[0056] When it comes to advantages, the present invention offers continuous and controlled release, improving the stability of vitamin D levels in the blood and facilitating adherence to treatment without the need for frequent administration.

[0062]

[0057] In summary, the use of resorbable polymers and organic solvents compatible with the human body in the prolonged release of vitamin D represents a significant advance over traditional forms of supplementation. This innovative approach improves efficacy, safety, and adherence to treatment, offering a superior solution for the prevention and treatment of vitamin D deficiency.

[0063]

[0058] It is worth noting that the inventive activity in question should be understood as representative and not limiting, and may be subject to convenient modifications and updates, provided that such modifications do not depart from the essence of the proposal.

Claims

CLAIMS 1. SLOW-RELEASE, LONG-ACTING SUBCUTANEOUS PHARMACEUTICAL FORMULATION FOR VITAMIN D RELEASE, CHARACTERIZED by the fact that the polymeric suspension of the in situ implant formed of 600,000 IU of Cholecalciferol (vitamin D3) contains 170 mg (42.5%) of Polycaprolactone (PCL) polymer and 215 mg (53.75%) of Dimethyl sulfoxide (DMSO) solvent for the administration of 15 mg (3.75%) of Cholecalciferol (vitamin D3), the mixing of the polymeric suspension with Cholecalciferol (vitamin D3) being carried out by a luer-lock system immediately before subcutaneous application, resulting in a daily release of 50 mcg of Cholecalciferol.

2. SUBCUTANEOUS PHARMACEUTICAL FORMULATION WITH SLOW RELEASE AND PROLONGED ACTION FOR VITAMIN D RELEASE, in accordance with claim 1, CHARACTERIZED in that the polymeric suspension of the in situ-formed implant of 500,000 IU of Cholecalciferol (vitamin D3) contains 160 mg (48.12%) of the polymer Poly(lactic-co-glycolic acid) (PLGA) and 160 mg (48.12%) of N-Methyl-2-Pyrrolidone (NMP) solvent for the administration of 12.5 mg (3.76%) of Cholecalciferol (vitamin D3), the mixing of the polymeric suspension of Cholecalciferol (vitamin D3) being carried out by a luer-lock system immediately before subcutaneous application, resulting in a daily release of 45 mcg of Cholecalciferol.

3. SUBCUTANEOUS PHARMACEUTICAL FORMULATION WITH SLOW RELEASE AND PROLONGED ACTION FOR VITAMIN D RELEASE, in accordance with claim 1, CHARACTERIZED in that the polymeric composition of the bioabsorbable implant containing 300,000 IU of Cholecalciferol (vitamin D3) has 2.5 mg (4%) of Polyvinylpyrrolidone (PVP) polymer, 22.5 mg (36%) of polylactic acid (PLA) polymer and 30 mg (48%) of magnesium stearate plasticizer mixed with 7.5 mg (12%) of cholecalciferol (vitamin D3), the vitamin D along with the polymers and the plasticizer in their dry forms being homogenized and added to a punch die where a mechanical force is applied to compress the particles, resulting in the daily release of 25 mcg of cholecalciferol.

4. SUBCUTANEOUS PHARMACEUTICAL FORMULATION WITH SLOW RELEASE AND PROLONGED ACTION FOR VITAMIN D RELEASE, in accordance with claim 1, CHARACTERIZED in that the polymeric composition of the bioabsorbable implant containing 2,000,000 IU of Cholecalciferol (vitamin D3) has 100 mg (50%) of Poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 50 mg (25%) of Polycaprolactone (PCL) polymer mixed with 50 mg (25%) of Cholecalciferol (vitamin D3), the mixture being extruded, heated, cut, transported, cooled to room temperature on a conveyor belt and cut to the established dimensions, resulting in the daily release of 50 mcg of Cholecalciferol.

5. SUBCUTANEOUS PHARMACEUTICAL FORMULATION WITH SLOW RELEASE AND PROLONGED ACTION FOR VITAMIN D RELEASE, in accordance with claim 1, CHARACTERIZED in that the polymeric composition of the bioabsorbable implant containing 1,200,000 IU of Cholecalciferol (vitamin D3) has 87.6 mg (73%) of Poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 2.4 mg (2%) of Mannitol plasticizer mixed with 30 mg (25%) of Cholecalciferol (vitamin D3), the mixture being ground to obtain 2 mm granules, extruded, heated, cut, transported, cooled to room temperature on a conveyor belt and cut to the established dimensions, resulting in a daily release of 25 mcg of Cholecalciferol.

6. SUBCUTANEOUS PHARMACEUTICAL FORMULATION WITH SLOW RELEASE AND PROLONGED ACTION FOR VITAMIN D RELEASE, in accordance with claim 1, CHARACTERIZED in that the injectable liquid preparation containing 600,000 IU of Cholecalciferol (vitamin D3) has 5 mg (0.5%) of Poly(lactic-co-glycolic acid) (PLGA) polymer (85:15) and 10 mg (1%) of NMP solvent mixed with 15 mg (1.5%) of Cholecalciferol (vitamin D3) and 970 mg (97.0%) of sunflower oil, the mixture being homogenized by heating for complete homogenization and packaged in 2 ml capacity ampoules, resulting in the delayed release of 15 mg of Cholecalciferol.

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