Administering cholecalciferol transdermally

Abstract

Disclosed are methods for increasing a patient's levels of vitamin D through transdermal administration of cholecalciferol. The patient may be identified as being at risk of calcidiol accumulation, such as having chronic kidney disease or being at risk of developing chronic kidney disease. The patient is administered a transdermal formulation of cholecalciferol. The transdermal formulation beneficially increases serum calcitriol in the patient without disproportionally accumulating serum calcidiol.

Description

ADMINISTERING CHOLECALCIFEROL TRANSDERMALLYBACKGROUNDTechnical Field

[0001] This disclosure is related to methods for treating vitamin deficiency in patients, particularly methods for transdermal supplementation of cholecalciferol.Related Technology

[0002] Vitamin D is a fat-soluble vitamin that is found in food and is also made in the body after exposure to ultraviolet (UV) rays from the sun. Sunshine is a significant source of vitamin D because UV rays from sunlight trigger vitamin D synthesis in the skin. Vitamin D exists in several forms, each with a different level of activity.

[0003] Vitamin D insufficiency is recognized as a cause of metabolic bone disease in adults that is characterized by the impairment of calcium and phosphate absorption. Sustained vitamin D insufficiency and deficiency are considered to be an important cause of impaired bone mineralization and gradual bone loss. Vitamin D3 (cholecalciferol) deficiency is implicated in numerous disorders. Cholecalciferol has been known to be intimately associated with regulation of calcium levels and bone metabolism and is implicated in osteomalacia, osteoporosis, osteopenia, fibrogenesis imperfecta ossium, and rickets. Cholecalciferol increases calcium absorption from the gut and consequently plasma calcium and suppresses secondary hyperparathyroidism and its skeletal consequences.

[0004] Exogenous Vitamin D is available through oral supplementation. However, despite the availability of oral supplementation of vitamin D, many individuals remain vitamin D deficient. Accordingly, additional methods for treating vitamin D-deficient individuals are needed.SUMMARY

[0005] Disclosed are methods for increasing levels of calcitriol in a patient. The method comprises identifying a patient as being at risk of calcidiol accumulation from oral supplementation of cholecalciferol and administering a transdermal formulation of cholecalciferol to the patient. The transdermal formulation can beneficially increase serum calcitriol in the patient without disproportionally accumulating serum calcidiol. As used herein, “without disproportionally accumulating serum calcidiol” means that the patient’s serum calcidiol levels stay approximately similar to the patient's calcitriol levels during atreatment period. For example, the patient's serum calcidiol levels stay within 2 times the patient's calcitriol levels, or within 1.8 times, or 1.6 times, or 1.4 times, or 1.2 times the patient's calcitriol levels during the treatment period, such as differing by no more than 15%, or 12.5%, or 10% from the patient's calcitriol levels.

[0006] The patient may, for example, be identified as having chronic kidney disease or at risk of developing chronic kidney disease and thus as being particularly susceptible to calcidiol accumulation from oral supplementation of cholecalciferol.

[0007] The patient may be identified as having (or as being at risk of developing) chronic kidney disease based on the patient’s estimated glomerular filtration rate. For example, the patient may have an estimated glomerular filtration rate of less than 60 mL / min / 1.73 m2. The patient may additionally or alternatively be identified as having (or as being at risk of developing) chronic kidney disease based on the patient’s urine albumincreatinine ratio. For example, the patient may have a urine albumin-creatinine ratio of 30 mg / g or more.

[0008] The disclosed methods can also be beneficial for patients that additionally or alternatively suffer from one or more other conditions. For example, the patient may further be identified as having secondary hyperparathyroidism and / or gastrointestinal malabsorption. The patient may additionally or alternatively be identified as having chronic liver disease. The patient may additionally or alternatively be identified as having a relatively high amount of melanin. The patient may additionally or alternatively be identified as having a swallowing impediment.

[0009] The transdermal cholecalciferol formulation may comprise a cream, lotion, spray, balm, salve, oil, foam, gel, or ointment. The transdermal formulation may additionally or alternatively comprise a patch. The patch may be configured to provide an extended release of cholecalciferol to a surface of the patient’s body. The patch is configured to be applied to a portion of a patient’s body having little to no hair or a portion of the patient’s body having a relatively lower hair density.

[0010] The patient may be instructed to vary an adhering location of a patch from an adhering location of a previous patch. The patch may be configured to be applied to an upper arm of the patient, for example. The method may include administration of the transdermal cholecalciferol formulation daily.

[0011] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is notintended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an indication of the scope of the claimed subject matter.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Various objects, features, characteristics, and advantages of the invention will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings and the appended claims, all of which form a part of this specification. In the Drawings, like reference numerals may be utilized to designate corresponding or similar parts in the various Figures, and the various elements depicted are not necessarily drawn to scale, wherein:

[0013] Fig. 1 illustrates the metabolic pathway of exogenous cholecalciferol when administered orally.

[0014] Fig. 2 illustrates the results of a study evaluating the change in certain vitamin D levels in individuals resulting from transdermal administration of cholecalciferol over a period of eight weeks.

[0015] Fig. 3 illustrates calcidiol and calcitriol levels in a porcine study evaluating the differences in oral supplementation and transdermal administration of cholecalciferol.

[0016] Fig. 4 is a flowchart of an example method for increasing blood levels of calcitriol in a patient.

[0017] Fig. 5 is an example chart that may be used to identify patients having or at risk of chronic kidney disease.DETAILED DESCRIPTIONIntroduction

[0018] Disclosed are methods for increasing calcitriol levels in patients, including patients at risk of excess accumulation of calcidiol upon oral supplementation of cholecalciferol. Vitamin D, in its biologically active form, is a hormone that regulates gene expression to thereby maintain calcium and inorganic phosphate homeostasis. Vitamin D binds to vitamin D receptors within the cell nuclei to regulate gene expression of transport proteins involved in calcium and phosphate absorption in the intestines. In this manner, vitamin D maintains calcium levels to promote bone formation, maintain bone density, and prevent bone fracture and osteoporosis. Low vitamin D levels have thus been associated with rickets, osteoporosis, and osteomalacia.

[0019] Vitamin D also has important effects on the cardiovascular, central nervous, endocrine and immune systems, and also plays an important role within cell differentiation and cell growth. For example, vitamin D plays an important role in stabilizing andrepairing neurons. Vitamin D also modulates chemokines via immune and inflammation pathways. Vitamin D may be used to treat or prevent psoriasis and is important for preventing other autoimmune diseases, including osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Vitamin D deficiency may cause various neurological symptoms, with healthy vitamin D homeostasis being important for preventing fatigue, depression, neurodegeneration, schizophrenia, and other cognitive disorders.

[0020] Low vitamin D levels have been associated with some forms of cancer (e.g., colorectal cancer, melanoma, prostate, breast, and bone cancer), inflammatory bowel disease, and attention deficit hyperactivity disorder (ADHD). Maintenance of vitamin D may also be important for reducing the risk of type 2 diabetes and preventing complications during pregnancy.

[0021] Vitamin D may be formed endogenously via sun exposure to skin. Cutaneous synthesis of vitamin D may occur as cholesterol (7-dehydrocholesterol) is converted photochemically in the epidermis to vitamin D (specifically cholecalciferol). 7- dehydrocholesterol reacts with ultraviolet B (UVB) light at wavelengths between 290 nm and 315 nm, which breaks the B ring of 7-dehydrcholesterol to form pre-vitamin D, which then undergoes isomerization to form cholecalciferol.

[0022] In keratinocytes of the dermis (i.e., underlying layer of the skin), cholecalciferol is then converted to the biologically active form of vitamin D (i.e., calcitriol) and passed to the bloodstream. Generally, overdose of vitamin D from UV exposure is not possible because once vitamin D reaches equilibrium the skin breaks down and degrades vitamin D as quickly as it is created. For many individuals, 30 minutes of sun exposure twice a week (wherein the face, upper arms, and lower legs are exposed) is sufficient to generate the amount of vitamin D needed. Of course, this can vary according to latitude, cloud cover, seasonal variations in solar intensity, and individual differences in skin pigmentation.

[0023] It is estimated that more than one billion people are vitamin D-deficient or insufficient worldwide. This may be in part due to the reduced sun exposure due to sedentary lifestyles where individuals spend much of their time indoors. Sun exposure received through windows is generally insufficient to enable cutaneous production of vitamin D, as glass tends to almost completely block UVB light used to synthesize vitamin D. Vitamin D deficiency and insufficiency may also arise in many individuals due to migration to latitudes with greater variation in daytime length. These effects may beparticularly exacerbated in those who have relatively high amounts of melanin. Because melanin blocks UV rays from reaching much of 7-dehydrocholesterol in the skin, these individuals generally require greater amounts of sun exposure to generate the same level of vitamin D as those without increased levels of melanin.

[0024] Vitamin D may also be obtained exogenously. For example, Vitamin D may be introduced intravenously. However, intravenous supplementation of vitamin D may be time consuming and costly, requiring patients to travel to medical practitioners to elevate their vitamin D levels.

[0025] Vitamin D can also be obtained through the diet. Consumption of vitamin D3 - generally derived from animal sources, including meat (pork, beef, chicken, and fish) and dairy products - leads to increased calcium absorption compared to consumption of vitamin D2, which is generally derived from plant sources. Dietary intake of vitamin D is low in modem diets, leading to increases in observed vitamin D deficiency in many populations. Oral supplementation of vitamin D is also available but is not consistently used or provided to vitamin D deficient individuals. Moreover, as explained in more detail herein, oral supplementation of Vitamin D can have drawbacks associated with calcidiol accumulation, and this problem can be particularly acute in certain patient populations.The Risk of Calcidiol Accumulation from Oral Supplementation

[0026] Fig. 1 illustrates the metabolic pathway 10 of ingested vitamin D. Typically, orally supplemented vitamin D is provided in the form of cholecalciferol 12. In a first step of the metabolic pathway 10, cholecalciferol 12 is adsorbed through the gastrointestinal tract and delivered to the liver 14. There, cholecalciferol 12 is hydroxylated via 25- hydroxylase 16 (primarily the CYP2R1 enzyme) to the prohormone calcidiol (i.e., 25- hydroxyvitamin D (18)). The calcidiol is released into the bloodstream where it binds to an a-globulin carrier protein (i.e., the vitamin D-binding protein 20). Calcidiol is then carried to the proximal tubules of the kidneys 24. There, calcidiol undergoes a second hydroxylation and is converted via la-hydroxylase 22 (CYP27B1 enzyme) to calcitriol (i.e., 1,25-diydroxyvitamin D (26)) - the hormonal and biologically active form of vitamin D. Calcitriol is then released back to the bloodstream, where it is transported throughout the body, such as to the intestines, the kidneys 24, and bones. Unused calcidiol and calcitriol may be further catabolized in the kidneys 24 via the 25(OH)-24-hydroxylase (CYP24A1 enzyme) to form the biologically inactive metabolite calcitroic acid.

[0027] However, in the context of oral Vitamin D supplementation, this metabolic pathway may present particular risks to the patient, particularly for patients with impairedkidney function. While cholecalciferol and calcitriol have a relatively short half-life (approximately 24 hours and 2-6 hours, respectively), calcidiol has a long half-life of approximately 600 hours. That is, the conversion of calcidiol to calcitriol in the kidneys is often the limiting “bottleneck” of the pathway from orally supplemented cholecalciferol to active calcitriol. This may lead to a dangerous accumulation of calcidiol, particularly for those patients who cannot metabolize calcidiol at sufficiently-high rates.

[0028] Consider, for example, a patient having impaired kidney function and who is vitamin D deficient. As the patient consumes orally supplemented cholecalciferol (whether animal-based, plant-based, or synthetic), the cholecalciferol will be absorbed through the intestines and converted to calcidiol at the liver. However, the reduced function of the kidneys may prevent the patient from effectively converting calcidiol to calcitriol at a rate sufficient to avoid accumulation of calcidiol. As the patient continues to consume cholecalciferol, an accumulation or buildup of calcidiol within the body may occur. This accumulation may cause an overdose of calcidiol in the patient, resulting in hypervitaminosis, toxicity, or other adverse effects. Thus, oral consumption of vitamin D may not always be the best or safest method of treating vitamin D-deficient individuals.Transdermal Administration of Cholecalciferol

[0029] Fig. 2 illustrates the results of a study analyzing transdermal administration of cholecalciferol to a pool of subjects. The results illustrate that transdermal vitamin D can be effective for increasing serum vitamin D levels. In the study, patients were identified as having either normal, low, or deficient levels of vitamin D (as determined by a measurement of serum vitamin D) and were administered a daily transdermal formulation of cholecalciferol in the form of a patch.

[0030] At the beginning of the study, the size of the vitamin D-deficient, low vitamin D, and normal vitamin D patient groups were comparable, with more than half of the participants being classified as having either low or deficient levels of vitamin D. As the study progressed, the number of patients in the vitamin D-deficient group decreased, with the number of patients having normal vitamin D levels increasing over time, and the number of patients having low vitamin D levels ultimately decreasing by the end of the 8- week study. As the patients’ vitamin D levels increased, most of the patients were categorized as having normal vitamin D levels by the end of the 8-week study period, with a total elimination of patients from the group exhibiting vitamin D deficiency.

[0031] While this study illustrated that a transdermal route of administration could effectively increase serum levels of Vitamin D, it was not yet known what additional advantages a transdermal route could provide over conventional oral supplementation.

[0032] Fig. 3 illustrates the results of a pharmacokinetic study comparing levels of calcidiol and calcitriol in serum samples collected from pig subjects administered cholecalciferol via oral or transdermal routes. The study illustrates the calcidiol measurements 42 and the calcitriol measurements 46 collected in a first porcine group, which was administered an oral supplement of cholecalciferol, and the calcidiol measurements 44 and the calcitriol measurements 48 collected in a second porcine group, which was administered a transdermal formulation of cholecalciferol.

[0033] The calcitriol measurements 46, 48 increased substantially in both the first and second porcine groups over the administration period of eight days (administration began on day 0). However, the calcidiol measurement 42 of the first porcine group increased substantially over the 8-day administration period, whereas the calcidiol measurement 44 of the second porcine group remained low. Calcidiol accumulation was only exhibited in the first porcine group (oral supplementation) and was not exhibited in the second porcine group (transdermal administration). Thus, a transdermal application may provide lower and safer levels of calcidiol when compared to the potential calcidiol accumulation and overdose of oral supplementation.

[0034] While not bound to any specific theory, it is believed that transdermal administration of cholecalciferol beneficially utilizes keratinocytes in the conversion of cholecalciferol to calcitriol, thus bypassing (at least to some extent) the function of the kidneys in converting calcidiol to calcitriol. Accordingly, this significantly reduces or avoids the risk of calcidiol accumulation in the patient.

[0035] Fig. 4 illustrates a method 100 for increasing the vitamin D levels of a vitamin D deficient patient. In a first step 110, a patient at risk of calcidiol accumulation from oral supplementation of cholecalciferol is identified, and in a second step 120, the patient is administered a transdermal formulation of cholecalciferol. In some instances, a patient may be at risk of calcidiol accumulation because of a chronic condition. For example, the patient may be identified or diagnosed as having chronic kidney disease or being at risk of kidney disease.

[0036] Those who have impaired kidney function are at particular risk of calcidiol buildup. Though even healthy patients are at risk of excessive calcidiol accumulation resulting from oral supplementation of cholecalciferol due to the bottleneck nature of theconversion of calcidiol to calcitriol in the kidneys, those with reduced kidney function are even less able to convert calcidiol to calcitriol and are therefore at even greater risk of excessive calcidiol accumulation.

[0037] Fig. 5 illustrates a chart 150 that can be used to identify those with chronic kidney disease or at risk of chronic kidney disease. Conventionally, an identification or diagnosis of chronic kidney disease may be performed by measuring two indicators: estimated glomerular filtration rate (GFR) and urine albumin-creatinine ratio (uACR). Generally, a GFR of 60 mL / min / 1.73 m2or less measured over 3 months or more may indicate an increased risk of chronic kidney disease . Similarly, a uACR of 30 mg / g or more measured over 3 months or more may indicate a patient has an increased risk of chronic kidney disease.

[0038] The chart 150 of Fig. 5 illustrates that the risk of chronic kidney disease increases with a decreasing GFR and an increasing uACR. Generally, a patient having 60 mL / min / 1.73 m2or more and a uACR of less than 30 mg / g - corresponding to the top two cells of the first column in the chart 150 of Fig. 5 (i.e., the cells labeled “A”) - may be considered at low risk of chronic kidney disease. Conversely, a patient having a measured GFR of less than 60 mL / min / 1.73 m2or a uACR of 30 mg / g or more may be identified as being at risk of chronic kidney disease. As the measured GFR decreases or as the measured uACR increases the risk of chronic kidney disease may also increase, with the cells labeled “B” indicating a moderate risk, cells labeled “C” indicating a high risk, and cells labeled “D” indicating a very high risk of chronic kidney disease.

[0039] In some embodiments, the patient may be identified as having chronic kidney disease (and thus as being at particular risk of calcidiol accumulation) if their measured GFR and uACR values fall into a cell labeled “B,” “C,” or “D.” In some embodiments, the patient may be identified as having chronic kidney disease (and thus as being at risk of calcidiol accumulation) if their measured GFR and uACR values fall into a cell labeled “C” or “D.” In some embodiments, the patient may be identified as having chronic kidney disease (and thus as being at risk of calcidiol accumulation) if their measured GFR and uACR values fall into a cell labeled “D.”

[0040] In some instances, chronic kidney disease may additionally or alternatively be identified in a patient using other indicators, including blood urea nitrogen (BUN), serum creatinine, microalbuminuria, or the results of a urinalysis. For example, a patient may be identified as having chronic kidney disease or at risk of developing chronic kidney disease if the patient has a BUN value above 21 mg / dL (for women) or above 24 mg / dL (for men),and / or a serum creatinine value above 1.1 mg / dL (for women) or above 1.3 mg / dL (for men).

[0041] In some embodiments, the method 100 may comprise identifying the patient as having a condition associated with or exacerbated by chronic kidney disease and / or a disease that may be mitigated with administration of vitamin D, such as secondary hyperparathyroidism (SHPT), metabolic acidosis, hyperphosphatemia, hyperkalemia, type 1 or type 2 diabetes, or nerve damage.

[0042] In some embodiments, the method 100 may comprise identifying the patient as having a condition wherein the efficacy of oral supplementation of vitamin D is reduced, and / or a disease wherein the patient has reduced ability to absorb or synthesize vitamin D. For example, the method 100 may comprise identifying the patient as having gastrointestinal malabsorption, celiacs disease, inflammatory bowel disease, and / or as having undergone gastric bypass surgery.

[0043] In another example, the patient may additionally or alternatively be identified as having a form of liver disease (e.g., chronic liver disease). Because ingested cholecalciferol is converted at the liver into calcidiol, those having liver disease may fail to adequately convert cholecalciferol to calcidiol and may not benefit from oral supplementation of cholecalciferol. Such patients may also benefit particularly from transdermal administration of cholecalciferol. The method 100 may comprise identifying the patient as having a chronic liver disease, such as, hepatitis, fibrosis, cirrhosis, or liver cancer (e.g., hepatocellular carcinoma).

[0044] In some embodiments, the method 100 may further comprise identifying the patient as having skin with relatively high levels of melanin (i.e., darker skin). The melanin in such individuals may block more ultraviolet rays compared to those with lighter / fairer skin, requiring those with greater quantities of melanin to receive more sun exposure. Such individuals may particularly benefit from transdermal administration of cholecalciferol if they are also at risk of calcidiol accumulation, such as those who suffer from or are at risk of chronic kidney disease. The patient may be identified as having relatively high levels of melanin using the Fitzpatrick phototype scale (which provides a scale from phototype I, indicating very low amounts of melanin, to phototype VI, indicating very high amounts of melanin). For example, the patient may be identified as having a skin type of phototype III or greater, or a skin type of phototype IV or greater, or a skin type of phototype V or greater, or a skin type of phototype VI on the Fitzpatrick phototype scale. Other skin tone scales may also be used, such as the melanin index (which uses skin reflectance to measuremelanin content), or other scales. For example, the patient may be identified as having a melanin index of approximately 60 or less, approximately 55 or less, or approximately 50 or less (e.g., when measured at the forehead or inner arm).

[0045] Certain conditions can benefit from high-dose vitamin D therapy. However, the relatively higher therapeutic doses recommended for such conditions can exacerbate the risk of calcidiol accumulation and hypervitaminosis. Accordingly, in some embodiments the method 100 can include identifying a patient undergoing high-dose vitamin D therapy or to which high-dose vitamin D therapy is recommended. A “high-dose” vitamin D therapy refers to a therapy where the dose exceeds the standard upper limit of 4,000 IU per day, though some studies suggest that amounts of 50,000 IU per day are tolerable. Accordingly, a “high-dose” vitamin D therapy can be defined herein as a therapy that involves a dose of 10,000 IU per day or greater, 15,000 IU per day or greater, 20,000 IU per day or greater, 25,000 IU per day or greater, 30,000 IU per day or greater, 35,000 IU per day or greater, 40,000 IU per day or greater, 45,000 IU per day or greater, or 50,000 IU per day or greater.

[0046] Examples of high-dose vitamin D therapies that can benefit from the disclosed methods include vitamin D treatment of pain conditions such as fibromyalgia, chronic musculoskeletal pain, or neuropathic pain (e.g., diabetic neuropathic pain). For example, Eombardo M, et al. ((2022) “The Efficacy of Vitamin D Supplementation in the Treatment of Fibromyalgia Syndrome and Chronic Musculoskeletal Pain. Nutrients” 14(15):3010) reported that fibromyalgia symptom relief was enhanced when serum levels of vitamin D surpassed 50 ng / mL. In addition, Basit A, et al. ((2016) Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Research & Care) reported that a single intramuscular dose of 600,000 IU of vitamin D in patients with painful diabetic neuropathy is associated with a significant decrease in pain symptoms. Other examples of high-dose vitamin D therapies include those intended for cancer prevention and / or treatment. For example, Ng K, et al. ((2019) “High-dose vitamin D shows benefit in patients with advanced colorectal cancer.” Dana-Farber Cancer Institute) reported that supplementing chemotherapy with high doses of vitamin D may benefit patients with metastatic colorectal cancer by delaying progression of the disease. Other examples of high-dose vitamin D therapies include treatment of autoimmune conditions such as rheumatoid arthritis or multiple sclerosis. Guan Y, et al. ((2020) The Effect of Vitamin D Supplementation on Rheumatoid Arthritis Patients: A Systematic Review and Meta- Analysis. Frontiers in Medicine) reported that vitamin D treatment subgroups with doses greater than 50,000 IUshowed significant benefits. Sotirchos ES, et al. ((2020) Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology) reported that high- dose vitamin D3 supplementation (10,400 lU / day) significantly reduced annualized relapse rates compared to placebo. Patients that can benefit from high-dose vitamin D therapies such as these are also at enhanced risk of excessive calcidiol accumulation and can therefore particularly benefit from the treatment methods disclosed herein.

[0047] In a second step 120, the patient is administered a transdermal formulation of cholecalciferol. The transdermal formulation may comprise cholecalciferol at approximately 0.0005% to approximately 0.1%, or approximately 0.001% to approximately 0.05%, or approximately 0.002% to approximately 0.035%, or approximately 0.003% to approximately 0.02%, or approximately 0.004% to approximately 0.01%, or approximately 0.005% by weight, or a range having any two of the foregoing values as endpoints.

[0048] The transdermal formulation of cholecalciferol may include cholecalciferol at an effective dosage. For example, the transdermal formulation of cholecalciferol may include a dose of approximately 500 international units (IU) to approximately 10000 IU, or approximately 800 IU to approximately 5000 IU, or approximately 1200 IU to approximately 4000 IU, or approximately 1500 IU to approximately 3000 IU. The transdermal formulation may be formulated for an intended dosing of once per day (e.g., one transdermal patch per day), for example.

[0049] In some embodiments, the transdermal formulation may alternatively or additionally comprise calcitriol in quantities and / or dosages similar to that of cholecalciferol above.

[0050] In some embodiments, the transdermal formulation may comprise a cream, lotion, spray, balm, salve, oil, foam, gel, or ointment. In some embodiments, the transdermal formulation of cholecalciferol may comprise a patch (e.g., a transdermal patch). The patch may be advantageously configured to provide an extended release of cholecalciferol. For example, the patch may comprise a reservoir configured to provide cholecalciferol to the skin for an extended period. The patch may be configured to provide an extended release of cholecalciferol for approximately 2 hours to approximately 24 hours, or approximately 4 hours to approximately 18 hours, or approximately 6 hours to approximately 12 hours, or approximately 8 hours to approximately 10 hours, or within a range having any two of the foregoing values as endpoints.

[0051] The transdermal formulation may be configured for daily administration to the patient or the method may further comprise daily administration for a period of two to ten weeks, or four to eight weeks, or six weeks, or a period within a range using any two of the foregoing values as endpoints. In some cases, administration can continue indefinitely and / or as needed to achieve targeted serum vitamin D levels.

[0052] The transdermal formulation may be configured to be applied to a location of the body that may place the converted calcitriol quickly in circulation in the patient’s bloodstream. For example, the transdermal formulation may be configured to be applied to the upper arm, the upper leg, or the back or neck of the patient’s body. The transdermal formulation may be configured to be applied on a location of the body having little to no hair, or a location of the body least likely to exhibit hair or having a relatively low hair density. The method may further comprise varying the location of transdermal formulation administered to the body. That is, the method 100 may comprising varying an adhering location of a patch to be different from at least the adhering location of the immediately previous day’s patch.

[0053] A transdermal formulation may provide other benefits over alternative forms of vitamin D supplementation. For example, the patient may be identified as having an increased pill burden (e.g., from resistance to swallowing pills and / or pill fatigue). A transdermal formulation may reduce the pill burden experienced by patient, helping to increase the amount of patient compliance in adhering to the vitamin D administration and reducing patient confusion of pills for those who consume multiple medications, particularly the elderly. For example, the patient may be identified as one taking multiple different medications by pill daily, such as three, four, five, six, seven, eight, or more than eight different pills daily. A transdermal formulation may be more convenient as, at least in the case of a transdermal patch, the user can apply a single extended-release transdermal formulation that may provide cholecalciferol throughout the extended period, and which removes the need to carry pills during that period. The patient may also be identified as one who has a swallowing impediment or other complication related to difficulty consuming supplements or foods high in vitamin D.

[0054] Elevated levels of vitamin D may be toxic, generally in plasma concentration above 150 ng / mL. Vitamin D overdose may be most likely when vitamin D is delivered via oral supplementation. Beneficially, results of studies by the applicant have found that vitamin overdose in transdermal formulations (specifically patch applications) in dosages as high as 30,000 IU did not lead to elevated (i.e., toxic) levels of vitamin D.Additional Terms & Definitions

[0055] The treatment methods disclosed herein also inherently disclose the associated medical uses (including any described second medical uses) of the disclosed transdermal formulations.

[0056] While certain embodiments of the present disclosure have been described in detail, with reference to specific configurations, parameters, components, elements, etcetera, the descriptions are illustrative and are not to be construed as limiting the scope of the claimed invention.

[0057] Furthermore, it should be understood that for any given element of component of a described embodiment, any of the possible alternatives listed for that element or component may generally be used individually or in combination with one another, unless implicitly or explicitly stated otherwise.

[0058] When the terms “about,” “approximately,” “substantially,” or the like are used in conjunction with a stated amount, value, or condition, it may be taken to mean an amount, value or condition that deviates by less than 20%, less than 10%, less than 5%, less than 1%, less than 0.1%, or less than 0.01% of the stated amount, value, or condition. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0059] Any headings and subheadings used herein are for organizational purposes only and are not meant to be used to limit the scope of the description or the claims.

[0060] It will also be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” do not exclude plural referents unless the context clearly dictates otherwise. Thus, for example, an embodiment referencing a singular referent (e.g., “widget”) may also include two or more such referents.

[0061] It will also be appreciated that embodiments described herein may also include properties and / or features (e.g., ingredients, components, members, elements, parts, and / or portions) described in one or more separate embodiments and are not necessarily limited strictly to the features expressly described for that particular embodiment. Accordingly, the various features of a given embodiment can be combined with and / or incorporated into other embodiments of the present disclosure. Thus, disclosure of certain features relative to a specific embodiment of the present disclosure should not be construed as limitingapplication or inclusion of said features to the specific embodiment. Rather, it will be appreciated that other embodiments can also include such features.

[0062] The embodiments disclosed herein should be understood as comprising / including disclosed components and may therefore include additional components not specifically described. Optionally, the embodiments disclosed herein are essentially free or completely free of components that are not specifically described or disclosed. For example, the transdermal formulations disclosed herein may be essentially free or completely free of other active ingredients (e.g., other vitamins and / or forms of Vitamin D other than cholecalciferol).

[0063] An embodiment that “essentially omits” or is “essentially free of’ a component may include trace amounts and / or non-functional amounts of the component. For example, an “essentially omitted” component may be included in an amount no more than 2%, no more than 1%, no more than 0.1%, or no more than 0.01% by total weight of the composition.

[0064] A composition that “completely omits” or is “completely free of’ a component does not include a detectable amount of the component (i.e., does not include an amount above any inherent background signal associated with the testing instrument) when analyzed using standard compositional analysis techniques such as, for example, chromatographic techniques (e.g., thin-layer chromatography (TLC), gas chromatography (GC), liquid chromatography (LC)), or spectroscopy techniques (e.g., Fourier transform infrared (FTIR) spectroscopy).

Claims

CLAIMS1. A method for increasing levels of calcitriol in a patient, the method comprising: identifying a patient as being at risk of calcidiol accumulation from oral supplementation of cholecalciferol; and administering a transdermal formulation of cholecalciferol to the patient, wherein the transdermal formulation increases serum calcitriol without disproportionately accumulating serum calcidiol.

2. The method of claim 1, wherein the method further comprises identifying the patient as having chronic kidney disease or as being at risk of developing chronic kidney disease.

3. The method of claim 2, wherein the method further comprises identifying the patient as having an estimated glomerular fdtration rate of less than 60 mL / min / 1.73 m2.

4. The method of claim 2, wherein the method further comprises identifying the patient as having a urine albumin-creatinine ratio of 30 mg / g or more.

5. The method of claim 1, wherein the method further comprises identifying the patient as having secondary hyperparathyroidism.

6. The method of claim 1, wherein the method further comprises identifying the patient as having gastrointestinal malabsorption.

7. The method of claim 1, wherein the method further comprises identifying the patient as having chronic liver disease.

8. The method of claim 1, wherein the transdermal formulation of cholecalciferol comprises a patch.

9. The method of claim 8, wherein the patch is configured to provide extended release of cholecalciferol.

10. The method of claim 8, wherein the patch is configured to provide an extended release of cholecalciferol within a range of approximately 2 hours to approximately 24 hours, or approximately 4 hours to approximately 18 hours, or approximately 6 hours to approximately 12 hours, or approximately 8 hours to approximately 10 hours.

11. The method of claim 8, wherein the patch is configured to be applied to a portion of a patient’s body having little to no hair or a portion of the patient’s body having a relatively lower hair density.

12. The method of claim 1, wherein the transdermal formulation is configured to be applied to an upper arm of the patient.

13. The method of claim 1, wherein the transdermal formulation of cholecalciferol comprises a cream, lotion, spray, balm, salve, oil, foam, gel, or ointment.

14. The method of claim 1, wherein the transdermal formulation of cholecalciferol comprises a dosage of approximately 500 IU to approximately 10000 IU, or approximately 800 IU to approximately 5000 IU, or approximately 1200 IU to approximately 4000 IU, or approximately 1500 IU to approximately 3000 IU.

15. The method of claim 1, wherein the transdermal formulation of cholecalciferol is administered daily for a treatment period of a week or longer.

16. The method of claim 1, wherein the transdermal formulation comprises cholecalciferol at approximately 0.0005% to approximately 0.1%, or approximately 0.001% to approximately 0.05%, or approximately 0.002% to approximately 0.035%, or approximately 0.003% to approximately 0.02%, or approximately 0.004% to approximately 0.01%, or approximately 0.005% by weight.

17. The method of claim 1, wherein the patient’s serum calcidiol levels stay approximately similar to the patient's calcitriol levels during a treatment period.

18. The method of claim 17, wherein the patient's serum calcidiol levels stay within 2 times the patient's calcitriol levels, or within 1.8 times, or 1.6 times, or 1.4 times, or 1.2 times the patient's calcitriol levels during the treatment period, such as differing by no more than 15%, or 12.5%, or 10% from the patient's calcitriol levels.

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