Extended-release triamcinolone acetonide for treating osteoarthritis pain in patients with diabetes.

Abstract

Embodiments of the present disclosure relate to the use of a long-release formulation of triamcinolone acetonide for treating osteoarthritis pain in diabetic subjects. One aspect of the present disclosure relates to a method for treating osteoarthritis (OA) pain (e.g., knee OA pain) in diabetic subjects, comprising identifying or selecting subjects with diabetes mellitus (DM) at risk of developing hyperglycemia caused by intra-articular injection of corticosteroids, determining or obtaining information regarding the subjects' baseline blood glucose levels, and administering approximately 32 mg of a long-release formulation of triamcinolone acetonide (TA) to the subjects by a single intra-articular injection.

Description

Background Art

[0001] Background Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease characterized by intra-articular (IA) inflammation, degradation of articular cartilage, and degenerative changes in the perijoint and subchondral bone. Because more than 27 million Americans are affected, OA is the most common joint disease, and arthritis is the most common cause of physical disability in the United States (McDonough et al. Clin Geriatr Med. 2010 August; 26(3):387-399). These numbers are expected to increase as a result of aging, obesity, and sports injuries. OA generally affects large weight-bearing joints such as the knee and hip, but OA can also affect the shoulder, hand, foot, and spine. Subjects with OA can have joint pain, tenderness, stiffness, and restricted movement. As the disease progresses, OA becomes increasingly painful and debilitating and often requires total joint replacement. The knee is the most commonly affected joint, and knee OA is the leading cause of physical disability in adults (Peat et al. Ann Rheum Dis. 2001 Feb; 60(2):91-97).

[0002] Diabetes mellitus, also known as diabetes mellitus (DM), is estimated to affect 34.2 million people in the United States alone, with an estimated 26.8 million (10.2% of the population) formally diagnosed and approximately 7.3 million still undiagnosed (Centers for Disease Control [CDC's] National Diabetes Statistics Report for 2020). The prevalence of osteoarthritis (OA) is approximately 30% in the group with type 2 diabetes, of which approximately 17.2% have knee OA (Louati et al. RMD Open 2015;1:e000077). Therefore, identifying common mechanisms contributing to the development of diabetes and inflammatory diseases, including OA, is an active area of ​​research. For example, one study found that type 2 diabetes predicts joint stenosis in men with symptomatic OA (Eymard et al. Osteoarthr. Carti. 2015, 23, 851-859). Furthermore, hyperglycemia is hypothesized to contribute to the progression of OA through the production of advanced glycation end products, induction of oxidative stress, and activation of inflammatory mediators (Berenbaum, Ann. Rheum. Dis. 2011;70:1354-1356).

[0003] Currently, there is no cure for osteoarthritis (OA). The main goal of current interventions is to reduce opioid use and the likelihood of physical disability, while improving pain, physical health, and quality of life (QoL). Patients with knee OA typically receive conservative, non-surgical treatment for 50% of their lifetime after diagnosis, and total knee replacement is generally performed only in patients with end-stage disease.

[0004] The most common non-surgical interventions for knee osteoarthritis (OA) include physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), braces, opioids, IA corticosteroid injections, and intra-articular replacement therapy. IA corticosteroids are particularly recommended for short-term acute pain relief by organizations such as the American College of Rheumatology (ACR), the International Society for Research on Osteoarthritis, the European League Against Rheumatism (EULAR), and the American Academy of Orthopaedic Surgeons. (American Academy of Orthopaedic Surgeons, Evidence-based Clinical Practice Guideline, August 31, 2021, https: / / www.aaos.org / oak3cpg.) Within hours of conventional administration of corticosteroid preparations, a rapid and substantial outflow of corticosteroids from the joints may be observed, thus limiting the intended pain-reducing effectiveness and potentially causing systemic effects in patients. Furthermore, elevated blood glucose levels (also known as hyperglycemia) have been observed in diabetic patients for up to three weeks after such administration (Habib and Miari, J Clin Rheumatol. 2011;17:302-305). Hyperglycemia is defined by the American Diabetes Association as Level 1 (blood glucose levels between 180 mg / dL and 250 mg / dL) or Level 2 (blood glucose levels above 250 mg / dL). In one study, blood glucose levels significantly increased in 23% of subjects who received IA triamcinolone acetonide crystalline suspension to treat osteoarthritis of the knee, peaking 24–32 hours after injection and remaining elevated for 2.5–4 days post-injection. (Habib G. et al. Arthritis Rheumatol. 2014 Jan;66(1):230). Therefore, the potential loss of glycemic control poses a significant clinical challenge for patients with type 2 diabetes receiving IA corticosteroids. (Russell et al., Rheumatology 2018;57(12):2235-2241). Thus, alternative and effective treatments for osteoarthritis pain in diabetic patients remain needed. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] McDonough et al. Clin Geriatr Med. 2010 August; 26(3):387-399 [Non-Patent Document 2] Peat et al. Ann Rheum Dis. 2001 Feb; 60(2):91-97 [Non-Patent Document 3] Louati et al. RMD Open 2015;1:e000077 [Non-Patent Document 4] Eymard et al. Osteoarthr. Carti. 2015, 23, 851-859 [Non-Patent Document 5] Berenbaum, Ann. Rheum. Dis. 2011;70:1354-1356. [Non-Patent Document 6] American Academy of Orthopaedic Surgeons, Evidence-based Clinical Practice Guideline, August 31, 2021, https: / / www.aaos.org / oak3cpg. [Non-Patent Document 7] Habib and Miari, J Clin Rheumatol. 2011;17:302-305 [Non-Patent Document 8] Habib G. et al. Arthritis Rheumatol. 2014 Jan;66(1):230 [Non-Patent Document 9] Russell et al., Rheumatology 2018;57(12):2235-2241 [Summary of the Invention] [Means for Solving the Problems]

[0006] Summary One aspect of this disclosure is, Identifying or selecting individuals with diabetes mellitus (DM) who are at risk of developing hyperglycemia due to intra-articular injection of corticosteroids, To determine the baseline blood glucose level of the target, or to obtain information about the baseline blood glucose level of the target, The extended-release formulation of triamcinolone acetonide (TA), approximately 32 mg, is administered to the target via a single intra-articular injection. A method for treating pain associated with osteoarthritis (OA) in patients with diabetes (e.g., knee OA pain), including, The extended-release formulation of TA is an extended-release formulation of TA containing poly(lactic acid-co-glycol) acid (PLGA) microspheres in a molar ratio of 75:25 (for example, administered by 5 mL intra-articular injection). This invention relates to a method for reducing the percentage of time during a certain period after administration of a prolonged-release formulation of TA compared to administration of a 40 mg immediate-release formulation of TA to the target population.

[0007] Another aspect of this disclosure is: Identifying or selecting individuals with diabetes mellitus who are at risk of developing hyperglycemia due to intra-articular injection of corticosteroids, To determine the baseline blood glucose level of the target, or to obtain information about the baseline blood glucose level of the target, Approximately 32 mg of the extended-release formulation of TA is administered to the target via a single intra-articular injection. A method for treating pain in osteoarthritis, such as knee osteoarthritis, in patients with diabetes, The extended-release formulation of TA is an extended-release formulation of TA containing poly(lactic acid-co-glycol) acid (PLGA) microspheres in a molar ratio of 75:25 (for example, administered by 5 mL intra-articular injection). This invention relates to a method for reducing the likelihood that the administration of an extended-release formulation of TA will result in the target patient's blood glucose level exceeding 180 mg / dL or 250 mg / dL within a certain period after administration, compared to administration of a 40 mg immediate-release formulation of TA to the same patient.

Brief Description of Drawings

[0008] [Figure 1] Figure 1 shows the results of the percentage of time spent in four blood glucose ranges before and after intra-articular injection of an extended-release formulation of triamcinolone acetonide (TA-ER) compared to an immediate-release formulation of TA (TA-IR) described in Example 1.

[0009] [Figure 2] Figure 2 shows the change in glucose levels (mg / dL) measured by continuous glucose monitor (CGM) of the TA-ER treatment group compared to the TA-IR treatment, for the CGM blood glucose values of TA-ER and TA-IR on days -7 to 14 described in Example 1.

Modes for Carrying Out the Invention

[0010] Detailed Description Embodiments of the present disclosure relate to methods or uses of extended-release triamcinolone acetonide (TA) for the management of pain in osteoarthritis in diabetic subjects. The methods of use include selecting or determining a diabetic subject at risk of developing hyperglycemia for treatment. The methods or uses may further include determining the baseline blood glucose value of the subject prior to administration of TA, or obtaining information regarding the baseline blood glucose value of the subject. The methods or uses may further include continuously monitoring the blood glucose value of the subject after injection, for example using a continuous glucose monitoring (CGM) device, to determine the blood glucose value of the subject after administration over a period of time. The methods or uses described herein provide better glucose control and fewer glucose spikes compared to immediate-release TA, improving the quality of life of the patient.

[0011] Definitions The headings of the sections used herein are for purposes of organization only and should not be construed as limiting the subject matter described.

[0012] Unless otherwise noted, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise. Unless otherwise noted, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. The use of "or" or "and" means "and / or" unless otherwise noted. The use of the term "comprising" and other forms such as "include", "includes", and "included" is not limiting. The use of the term "having" and other forms such as "have", "has", and "had" is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claims, the terms "comprising" and "comprises" should be interpreted in an open-ended sense. That is, these terms should be interpreted as synonymous with the phrases "having at least" or "including at least". For example, when used in the context of a process, the term "comprises" means that the process includes at least the recited steps, but may also include additional steps. When used in the context of a compound, composition, formulation, or device, the term "comprises" means that the compound, composition, formulation, or device includes at least the recited features or components, but may also include additional features or components.

[0013] As used in this specification, "triamcinolone acetonide" or "TA" refers to a compound having the following structure:

Chemical formula

[0014] ​When used herein, the terms “immediate release” or “immediate-release” have their usual meanings as understood by those skilled in the art, and therefore include, in a non-limiting example, the release of a drug form from a dosage form within a relatively short period after administration.

[0015] The terms “extended release” or “extended release properties” are, when used herein, as they normally would be understood by those skilled in the art, and therefore include, in non-limiting examples, controlled release of a drug from a dosage form over a longer period of time. For example, in some embodiments, an extended-release formulation has a substantially longer release rate than the release rate of a comparable immediate-release form.

[0016] The terms “to treat,” “treatment,” or “to treat” as used herein refer to administering a pharmaceutical composition / formulation for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a patient who is not yet suffering from a disease but is susceptible to a particular disease or is at risk of developing a particular disease under other circumstances, thereby reducing the patient’s likelihood of developing the disease. The term “therapeutic treatment” refers to treating a patient who is already suffering from a disease.

[0017] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable additive” include all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and active ingredients for pharmaceutically active substances is well known in the art. Unless any conventional media or active ingredient is incompatible with the active ingredient, its use in a therapeutic composition or formulation is assumed. Supplementary active ingredients may also be incorporated into the composition or formulation. Furthermore, various additives commonly used in the art may be included. These compounds and other such compounds are listed in the literature, for example, in The Merck Index (Merck & Company, Rahway, NJ). Considerations regarding the inclusion of various ingredients in pharmaceutical compositions are, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0018] How to treat diabetic patients Some embodiments of the present disclosure relate to a method for treating or improving osteoarthritis pain (e.g., knee osteoarthritis pain) in diabetic subjects, comprising identifying or selecting subjects with diabetes mellitus (DM) at risk of developing hyperglycemia caused by intra-articular injection of corticosteroids, determining or obtaining information regarding the baseline blood glucose levels of the subjects, and administering to the subjects a certain amount of an extended-release formulation of triamcinolone acetonide (TA) by a single intra-articular injection.

[0019] Patient Selection In some embodiments of the methods described herein, subjects with diabetes mellitus (DM) at risk of developing hyperglycemia due to intra-articular injection of corticosteroids may also have type 2 diabetes. In some other embodiments, subjects may have type 1 diabetes. In some embodiments, subjects had type 2 or type 1 diabetes for at least 1, 2, 3, 6, 9, or 12 months prior to treatment. In some embodiments, subjects have been or are being treated with one or more antidiabetic agents (e.g., insulin injection and / or oral antidiabetic agents). In some further embodiments, subjects have been or are being treated with one or more antidiabetic agents in stable doses for at least 1, 2, or 3 months prior to treatment. In some embodiments, selected or identified subjects have a hemoglobin A1c (HbA1c) level of 9% or less before or at the start of treatment. In some further embodiments, the selected or identified subject has a hemoglobin A1c (HbA1c) level of 6.5% or higher and less than 9.0% prior to the initiation of treatment. In some embodiments, the subject is approximately 27 to approximately 45 kg / m². 2 They have a body mass index (BMI).

[0020] In some embodiments of the methods described herein, subjects had painful symptoms associated with knee osteoarthritis (OA) for at least 1, 2, 3, 4, 5, or 6 months prior to treatment. In some embodiments, subjects met the American College of Rheumatology (ACR) criteria (clinical and radiological) for OA as follows (Altman et al. Arthritis Rheum. 1986 Aug;29(8):1039-49). • Knee pain · Bone spurs • At least one of the following: 〇 Ages over 50 〇 Stiffness lasting less than 30 minutes 〇 A twisting sound. In some embodiments, the subjects had experienced index knee pain for most days (more than 15 days) over the preceding month prior to the initiation of treatment.

[0021] exclusion In some embodiments, subjects do not have Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease. In some embodiments, subjects do not have a history of infection at the originating knee joint. In some embodiments, subjects do not have clinical signs and symptoms of active knee infection or crystal disease at the originating knee within one month after selection or identification, or before the initiation of treatment.

[0022] In some embodiments, the subject has not been previously treated with one or more of the following drugs, or has been treated simultaneously with them: • IA corticosteroids in any joint within 1, 2, or 3 months prior to the start of treatment • IA hyaluronic acid in the knee at the time of onset within 1, 2, 3, 4, 5, or 6 months prior to the start of treatment. • Oral, intravenous (IV), or intramuscular (IM) corticosteroids administered within 1, 2, or 3 months prior to the start of treatment. • Inhalation, intranasal, or topical corticosteroids within 1, 2, or 3 weeks prior to the start of treatment, such as inhaled corticosteroids (including, but not limited to, budesonide, fluticasone, Alvesco®, mometasone, flunisolide, fluticasone propionate / salmeterol, fluticasone propionate, mometasone / formoterol, budesonide / formoterol, and Flovent® Diskus), Intranasal corticosteroids (azelastine / fluticasone intranasal, beclomethasone intranasal, Beconase® AQ, budesonide intranasal, ciclesonide intranasal, ClariSpray®, Dymista®, Flonase allergy relief, Flonase Sensimist allergy relief, flunisolide intranasal, FlutiCare®, fluticasone intranasal, mometasone intranasal, Nasacort® Allergy) 24HR, Nasonex (trademark), olopatadine intranasal / mometasone intranasal, Omnaris (registered trademark), QNASL (registered trademark), Rhinocort (registered trademark) Allergy, Rhinocort (registered trademark) Aqua (DSC), Ryaltris (registered trademark), triamcinolone intranasal, Veramyst (registered trademark), Xhance (registered trademark), and Zetonna (trademark), including but not limited to these, topical corticosteroids (betamethasone dipropionate, betamethasone valerate) This includes, but is not limited to, esters, clobetasol propionate, diflorasone diacetate, fluocinonide, flulandrenolide, halobetazole, amcinonide, desoxymethasone, halcinonide, fluticasone propionate, triamcinolone acetonide, desoxymethasone, hydrocortisone, hydrocortisone valerate, fluocinolone acetonide, mometasone furoate, alclometasone dipropionate, desonide, and fluocinolone.

[0023] In some embodiments, the subject has not undergone arthroscopic or open surgery on the originating knee within 3, 6, 9, or 12 months prior to the start of the procedure.

[0024] In some embodiments, if the subject monitors blood glucose levels using a continuous glucose monitoring device, the subject should not use acetaminophen or acetaminophen-containing products from the start of treatment until at least 7, 14, 21, or 28 days after the completion of treatment.

[0025] In any embodiment of the methods described herein, a specific or selected subject is at risk of developing hyperglycemia resulting from intra-articular (IA) injection of an immediate-release formulation of a corticosteroid, including but not limited to beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof. In a further embodiment, a subject may be at risk of having a glucose spike exceeding 180 mg / dL or 250 mg / dL at a longer period after IA injection of an immediate-release formulation of a corticosteroid (e.g., an immediate-release formulation of TA described herein) (e.g., within 24, 48, or 72 hours after IA injection). In further embodiments, subjects may have had glucose spikes exceeding 180 mg / dL or 250 mg / dL for a period of time (e.g., within 24, 48, or 72 hours after IA injection) following a previous immediate-release (IA) formulation of a corticosteroid (e.g., an immediate-release formulation of TA as described herein). In some further embodiments, specific or selected subjects may be at risk of having, or have experienced, glucose spikes exceeding 180 mg / dL or 250 mg / dL for at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of the time within 24, 48, or 72 hours after IA injection of an immediate-release (IA) formulation of a corticosteroid (e.g., an immediate-release formulation of TA as described herein).

[0026] Extended-release formulation of triamcinolone acetonide In some embodiments, the extended-release formulation of TA may be microsphere-based. In some further embodiments, the microsphere-based formulation may be TA (e.g., Zilretta®) in poly(lactic-co-glycol) acid (PLGA) microspheres with a molar ratio of 75:25. Zilretta® is formulated in PLGA microspheres containing a nominal drug load of 25% (w / w) with a molar ratio of lactic acid to glycolic acid of 75:25, and is provided as a sterile white to off-white powder. Zilretta® is prepared with a supply diluent containing an isotonic sterile aqueous solution of sodium chloride (NaCl, 0.9% w / w), sodium carboxymethylcellulose (CMC, 0.5% w / w), and polysorbate-80 (0.1% w / w) to form a 5 mL sterile suspension intended for intra-articular injection. In some embodiments, the extended-release formulation of TA is administered as a single intra-articular injection. In some such embodiments, the extended-release formulation of TA is supplied as a single-dose kit containing one vial of 75:25 poly(lactic acid-co-glycol) acid (PLGA) microsphere powder, one vial of 5 mL of diluent, and one sterile vial adapter. In some embodiments, the amount of the extended-release formulation of TA administered is in the range of approximately 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg, or one of the two aforementioned values. For example, the amount of the extended-release formulation of TA may be approximately 20 mg to approximately 25 mg, approximately 20 mg to approximately 40 mg, approximately 30 mg to approximately 35 mg, approximately 25 mg to approximately 35 mg, etc. In some embodiments, the amount of the extended-release formulation of TA is in the range of approximately 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, or 35 mg, or one of the two aforementioned values. In one embodiment, the amount of the extended-release formulation of TA is approximately 32 mg. In some embodiments, the extended-release formulation of TA may be administered as an intra-articular injection in volumes of approximately 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL. In some embodiments, the extended-release formulation of TA is 32 mg of TA administered as a 5 mL intra-articular injection.

[0027] In some embodiments, the starting knee is aspirated prior to drug administration. After aspiration, either the TA-ER drug or the TA-IR control drug is injected into the synovial space. The same needle used for the IA injection of the TA drug may also be used for synovial fluid aspiration, thereby enabling a single injection with syringe change. In some embodiments, a 21-gauge or larger needle may be used for fluid injection and aspiration.

[0028] In some embodiments of the methods described herein, administration of an extended-release formulation of TA may reduce the percentage of time spent above 180 mg / dL or 250 mg / dL during a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period. In some such embodiments, baseline blood glucose levels are first established or measured immediately before IA administration of the TA drug and monitored for at least 24, 48, or 72 hours immediately after TA administration. The percentage of time spent above a certain blood glucose level is calculated by dividing the amount of time the target blood glucose level is above 180 mg / dL or 250 mg / dL by the period during which the target blood glucose level is monitored. In some further embodiments, the percentage of time spent with blood glucose levels above 180 mg / dL or 250 mg / dL is reduced by at least approximately 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% during a certain period after TA administration, compared to administration of an immediate-release formulation of TA during the same period (e.g., 24 hours, 48 ​​hours, or 72 hours). In some further embodiments, the subject spends time with blood glucose levels above 180 mg / dL for approximately 25%, 20%, 15%, 10%, or 5% of a certain period after administration. In some further embodiments, the subject spends time with blood glucose levels above 250 mg / dL for approximately 25%, 20%, 15%, 10%, or 5% of a certain period after administration, or less.

[0029] In some embodiments of the methods described herein, administration of a prolonged-release formulation of TA may reduce the likelihood of the target blood glucose level exceeding 180 mg / dL or 250 mg / dL within a certain period after administration, compared to administration of an immediate-release formulation of TA. In some such embodiments, baseline blood glucose levels are first established or measured immediately before IA administration of the TA drug and monitored for at least 24, 48, or 72 hours immediately after TA administration to determine whether the target blood glucose level changes from baseline to exceed 180 mg / dL or 250 mg / dL during the monitoring period. In some further embodiments, the likelihood of the target blood glucose level exceeding 180 mg / dL or 250 mg / dL is reduced by at least approximately 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% over a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period (e.g., 24 hours, 48 ​​hours, or 72 hours).

[0030] In some embodiments of the methods described herein, administration of an extended-release formulation of TA may increase the time to reach a blood glucose level of 180 mg / dL or 250 mg / dL within a certain period after administration, compared to administration of an immediate-release formulation of TA. In some such embodiments, baseline blood glucose levels are first established or measured immediately before IA administration of the TA drug and monitored for at least 24, 48, or 72 hours immediately after TA administration to determine whether the blood glucose level of interest changes from baseline to above 180 mg / dL or 250 mg / dL during the monitoring period. In some further embodiments, the time to reach a blood glucose level of 180 mg / dL or 250 mg / dL is increased by at least approximately 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1x, 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, or 5x over a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period (e.g., 24 hours, 48 ​​hours, or 72 hours). In some further embodiments, the time to reach a blood glucose level of 180 mg / dL or 250 mg / dL may be increased by at least approximately 25%, 50%, 75%, 1x, 1.5x, 2x, 2.5x, 3x, 4x, or 5x over a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period (e.g., 24 hours, 48 ​​hours, or 72 hours).

[0031] In some embodiments, administration of an extended-release formulation of TA may also increase the time to reach maximal blood glucose within a certain period after administration, compared to administration of an immediate-release formulation of TA. In some such embodiments, baseline blood glucose is first established or measured immediately before IA administration of the TA drug and monitored for at least 24, 48, or 72 hours immediately after TA administration to determine whether the blood glucose of interest changes from baseline to maximal blood glucose during the monitoring period. In some further embodiments, the time to reach maximal blood glucose is increased by at least approximately 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1x, 1.5x, 2x, or 2.5x within a certain period after administration, compared to administration of an immediate-release formulation of TA during the same period (e.g., 24, 48, or 72 hours). In some further embodiments, the time to reach maximum blood glucose is increased by at least approximately 25%, 50%, 75%, 1x, 1.5x, 2x, or 2.5x over a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period (e.g., 24 hours, 48 ​​hours, or 72 hours).

[0032] In some embodiments of the methods described herein, administration of an extended-release formulation of TA may also increase the percentage of time spent within the target blood glucose range of 70 mg / dL or greater and 180 mg / dL or less during a certain period after administration, compared to administration of an immediate-release formulation of TA. In some such embodiments, baseline blood glucose levels are first established or measured immediately before IA administration of the TA drug and monitored for at least 24, 48, or 72 hours immediately after TA administration to determine the time during which the target blood glucose level is within the target blood glucose range during the monitoring period. In some further embodiments, the percentage of time spent within the target blood glucose range is increased by at least approximately 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1x, 1.5x, 2x, or 2.5x over a certain period after administration, compared to administration of an immediate-release formulation of TA over the same period (e.g., 24 hours, 48 ​​hours, or 72 hours).

[0033] In some embodiments of the methods described herein, the consumption of the target antidiabetic agent (e.g., insulin consumption) after administration of the extended-release formulation of TA is less than the consumption of the target antidiabetic agent (e.g., insulin consumption) after administration of 40 mg of the immediate-release formulation of TA over a certain period after administration. In some further embodiments, the consumption of the antidiabetic agent is reduced by at least about 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% over a certain period after administration compared to the same period after administration of the immediate-release formulation of TA. The certain period may be up to two weeks (e.g., day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, or day 14). In some such embodiments, the consumption of the target antidiabetic agent (e.g., insulin consumption) is increased from baseline (72 hours prior to administration), but such increase is smaller than the increase in antidiabetic agent consumption (e.g., insulin consumption) after administration of 40 mg of the immediate-release formulation of TA.

[0034] In some embodiments of the methods described herein, the mean daily knee pain intensity score (at the initiating knee) of a subject over a certain period following administration of the extended-release formulation of TA is lower than the mean daily knee pain intensity score over a certain period following administration of 40 mg of the immediate-release formulation of TA.

[0035] In any embodiment of the method described herein, the baseline blood glucose level of the subject is measured or information regarding the baseline blood glucose level of the subject is obtained within approximately 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours prior to injection.

[0036] In any embodiment of the method described herein, the post-administration period may be approximately or at least approximately 24 hours (1 day), approximately 48 hours (2 days), approximately 72 hours (3 days), approximately 96 hours (4 days), approximately 120 hours (5 days), approximately 144 hours (6 days), 168 hours (7 days), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In one embodiment, the post-administration period is approximately 72 hours. In further embodiments, the subject is continuously monitored after TA treatment for the entire period. In one embodiment, continuous monitoring is performed by a CGM device (e.g., a Dexcom Professional CGM device).

[0037] Immediate-release formulation of triamcinolone acetonide In any embodiment of the methods described herein, the immediate-release formulation of TA (TA-IR) for comparison is for administration by intra-articular injection. In some embodiments, the amount of the immediate-release formulation of TA for comparison is about 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, or 45 mg. In one embodiment, the amount of the immediate-release formulation of TA for comparison with the extended-release formulation of TA described herein is about 40 mg. In further embodiments, immediate-release formulations of TA for comparison are for administration in volumes of approximately 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL, at concentrations of approximately 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, or 60 mg / mL. In one embodiment, the immediate-release formulation of TA is administered as a 1 mL intra-articular injection. In some embodiments, the immediate-release formulation of TA is a 40 mg / mL injectable suspension (Kenalog®-40) administered as a 1 mL intra-articular injection. Each 1 mL of sterile aqueous suspension of Kenalog®-40 contains 40 mg of triamcinolone acetonide together with sodium chloride, sodium carboxymethylcellulose, and polysorbate 80 for isotonicity. Benzyl alcohol, a preservative, may also be present. Sodium hydroxide or hydrochloric acid may be present to adjust the pH to 5.0-7.5.

[0038] In any of the embodiments described herein, the subject having diabetes mellitus may be managed prior to treatment with one or more antidiabetic agents, such as injectable or oral antidiabetic agents, or both. In some further embodiments, the method may also include adjusting the dosage of one or more antidiabetic agents if the subject's blood glucose level exceeds the target blood glucose range of 70 mg / dL or higher and 180 mg / dL or lower. [Examples]

[0039] The following embodiments are non-limiting and merely represent various aspects of the present disclosure.

[0040] (Example 1) This example summarizes the results of a randomized, parallel-group, double-blind phase 2 study (NCT02762370) and a clinical study comparing the effects of extended-release (TA-ER) and immediate-release (TA-IR) triamcinolone acetonide on blood glucose (BG) in patients with osteoarthritis of the knee and type 2 diabetes mellitus.

[0041] research design Eligible participants at screening had symptomatic knee osteoarthritis (OA) for at least 6 months, type 2 diabetes for at least 1 year, met the American College of Rheumatology's clinical and radiological criteria for OA, and had a hemoglobin A1c level (HbA1c) of 6.5% or higher and less than 9.0%. Participants were randomized to receive either TA-ER or TA-IR IA injections. Continuous glucose monitoring (CGM) provided portable glucose profiles (AGPs) summarizing BG levels for each participant before and over 14 days after IA injection.

[0042] Patients were randomized to receive either TA-ER 32 mg (Zilretta® 5 ml) or TAc 40 mg (Kenalog®-40, Bristol-Myers Squibb Company, Princeton, NJ, USA; 1 ml) as an IA dose. Eighteen patients were treated with TA-ER and fifteen with TA-IR. TA-ER and TA-IR did not look identical at the time of administration. Therefore, treatments were prepared and administered by staff at a designated open-label facility with no contact with participants or researchers, and the injection syringes were concealed from the study participants. After screening (days -21 to -7), CGMG data (Dexcom G4 Platinum Professional CGM) were collected from pre-treatment (days -7 to 0) to two weeks post-injection (days 0 to 14), as described above. Day 0 was the injection day.

[0043] In this post-hoc analysis, participant data were categorized by the internationally recognized threshold for severe (level 2) hyperglycemia (i.e., BG levels above 250 mg / dL). Mean daily glucose level change from baseline, mean time within or above the target range of 70–180 mg / dL, and glucose variability at multiple time points were also examined. Time above range (TAR) was compared between groups over four study periods: pre-injection days 7–0 and -3–0, and post-injection days 1–3 and 4–14. Kaplan-Meier analyses were performed to determine the time required to reach 250 mg / dL and the time to reach maximum glucose levels. HbA1c levels were estimated from CGM data using a glucose management indicator (GMI) according to a published, validated algorithm.

[0044] result Figure 1 shows the results of the percentage of time spent in four blood glucose ranges before and after intra-articular injection of extended-release TA (TA-ER) compared to immediate-release TA (TA-IR). From top to bottom in each column of the figure, the ranges are defined as BG levels above 250 mg / dL, BG levels above 180 mg / dL and below 250 mg / dL, BG levels above 70 mg / dL and below 180 mg / dL, and BG levels below 70 mg / dL. During the study period from 1 to 3 days post-injection, the mean percentage of TAR above 250 mg / dL (12%) in the TA-ER group was reduced by half compared to the TA-IR group (26%), and the percentage of time spent in the target range (70 mg / dL to 180 mg / dL) was higher for the TA-ER group (62%) compared to the TA-IR group (48%) (see Figure 1). The TA-ER group also had a significantly lower proportion of subjects (50%) who experienced a maximum CGM glucose level exceeding 250 mg / dL over days 1-3 compared to the TA-IR group (93%).

[0045] Figure 2 shows the change in glucose levels (mg / dL) measured by continuous glucose monitoring (CGM) in the TA-ER treatment group compared to the TA-IR treatment group for TA-ER and TA-IR from days 7 to 14. The median glucose level is shown as a thick line, the median glucose level ± mean absolute deviation (MAD) as a thin line, the target range limit as a dashed line, and the injection day as a solid fill. The dashed line at 250 mg / dL indicates the threshold for severe hyperglycemia. The dashed line between 180 mg / dL and 70 mg / dL indicates the target glucose threshold. AGP analysis showed that the TA-ER group exhibited more consistent glucose levels and smaller glucose level spikes throughout the study (see Figure 2). A similar trend was observed for further AGP output performed on fasting glucose at 7 a.m. The median time to 250 mg / dL (TA-ER, 44 hours; TA-IR, 6 hours; P=0.003) and time to peak glucose level (TA-ER, 34 hours, peak glucose level range, 154–390 mg / dL; TA-IR, 13 hours, peak glucose level range, 206–401 mg / dL; P=0.007) were significantly more favorable for TA-ER compared to TA-IR. Estimated mean GMI values ​​were numerically lower (7.1 vs. 7.5) for TA-IR over days 0–14, although not statistically significant.

[0046] This analysis suggests that TA-ER was associated with a clinically meaningful reduction in hyperglycemia compared to TA-IR. The reduction in glucose level spikes observed in the TA-ER group suggests that TA-ER may lead to fewer short-term hyperglycemia-related adverse events. The increased duration within the target range of 70 mg / dL to 180 mg / dL is expected to improve glucose management after IA injections, particularly in patients requiring repeated corticosteroid injections for the management of OA knee pain. The reduction in time spent at glucose levels above 250 mg / dL is expected to improve patient well-being and reduce the use of healthcare resources. Since HbA1c is a key indicator of glucose control and estimation of long-term complications, the reduction in GMI observed in the TA-ER group compared to the TA-IR group suggests that TA-ER may help reduce the risk of these complications.

[0047] (Example 2) This example summarizes a phase IV randomized, double-blind, active-controlled study to evaluate the effects of Zilretta® (triamcinolone acetonide extended-release, TA-ER) and TA-IR (triamcinolone acetonide immediate-release) on blood glucose in patients with osteoarthritis of the knee and diabetes mellitus. The objective of this phase IV study was to evaluate the continuous glucose monitoring (CGM) pattern for TAR exceeding 250 mg / dL from baseline to days 0-3 after a single IA injection of TA-ER 32 mg compared to TA-IR 40 mg. This study is also intended to address the following objectives: (1) characterizing fasting blood glucose (FBG) variability over the entire study period using CGM-derived AGP analysis for a single IA injection of TA-ER 32 mg compared to TA-IR 40 mg; (2) evaluating the difference in time-dependent maximum hyperglycemic distance after a single IA injection of TA-ER 32 mg compared to TA-IR 40 mg; (3) evaluating the safety and general tolerability of a single IA injection of TA-ER 32 mg compared to TA-IR 40 mg; (4) characterizing hyperglycemia patterns over the study period using CGM-derived AGP analysis for a single IA injection of TA-ER 32 mg compared to TA-IR 40 mg; (5) evaluating the acute effect of hyperglycemia on quality of life (QoL) of treatment with TA-ER 32 mg compared to TA-IR 40 mg; and (6) using 14-day CGM blood glucose study data to characterize TA-IR Quantify the GMI index for TA-IR 32mg compared to 40mg.

[0048] research design Eligible participants are at least 40 years old and have symptomatic knee osteoarthritis and diabetes mellitus managed with either an injectable or oral antidiabetic agent, or both. Approximately 20% of the target population includes type 1 diabetes. Participants should have been on a stable dose of injectable or oral medication for at least two months prior to study screening and should have an HbA1c level of 6.5%–9.0% at screening. Approximately 140 participants should be randomized (1:1) to one of two treatment groups, treated with either TA-ER 32 mg or TA-IR 40 mg. BG levels for each participant should be collected and evaluated over a total of three weeks, spanning one week before injection and two weeks after injection.

[0049] Following screening visits, subject BG levels will be measured up to one week before injection and two weeks after injection using a Dexcom G6 Pro "Masked" CGM device set to blinded mode. Co-primary endpoint analysis should be based on CGM-derived BG data up to 72 hours post-treatment. Secondary and exploratory endpoint analysis should be based on CGM-derived FBG-AGP analysis for the entire study period.

[0050] Treatment arm The treatment arm includes the following: A 32 mg extended-release formulation of triamcinolone acetonide in 75:25 PLGA (poly(lactic acid-co-glycolic acid)) microspheres, administered as a 5 mL IA knee injection. A 40 mg immediate-release formulation of triamcinolone acetonide injection suspension, administered as a 1 mL 1A knee injection.

[0051] Inclusion Criteria During the screening period (unless otherwise specified below), each participant must meet all of the following criteria to be enrolled in this study: 1. A man or woman who is at least 40 years old. 2. Type 1 or type 2 diabetes for at least one year prior to screening. 3. The patient has been currently treated with a stable dose of an injectable and / or oral antidiabetic agent for at least two months prior to screening. 4. HbA1c level of 6.5% or higher and less than 9.0% at the time of screening. 5. Painful symptoms associated with knee osteoarthritis for at least six months prior to screening. 6. Currently meets the American College of Rheumatology's criteria for OA (clinical and radiological) (Altman et al, 1986): • Knee pain • At least one of the following: • Ages over 50 • Stiffness lasting less than 30 minutes • Twisted hair sound · Bone spurs. 7. Originating knee pain (reported by the subject) on most days (more than 15 days) over the past month. 8. Body Mass Index (BMI) 27-45 kg / m² 2 .

[0052] Exclusion criteria Participants who meet any of the following criteria (except as specified below during the screening period) will be excluded from this study: 1. Arthritis associated with Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease. 2. A medical history of the initial knee joint infection. 3. Clinical signs and symptoms of an active knee infection or crystalline disease of the originating knee within one month of screening. 4. The presence of surgical hardware or other foreign objects in the knee at the time of the injury. 5. Joint instability within 12 months of screening (e.g., anterior cruciate ligament rupture). 6. IA corticosteroid (investigative or commercially available) in any joint within 3 months of screening. 7. IA hyaluronic acid (in clinical trials or commercially available) in the knee at the time of screening within 6 months prior to the screening. 8. IV or IM corticosteroid (investigative or marketed) within 3 months of screening. 9. Oral corticosteroids (in clinical trials or commercially available) within one month of screening. 10. Inhalation, intranasal, or topical corticosteroids (investigative or commercially available) within two weeks of screening. 11. Any other IA investigational drug / biologic with a half-life of 6 months or 5 months (whichever is longer) within the screening period. 12. Arthroscopic or open surgery of the knee at the time of the initial injury within 12 months of the screening. 13. Planning / scheduling of any initial knee surgery or any other surgery during the study period. 14. Use of acetaminophen or acetaminophen-containing products from screening to day 14 (completion of post-treatment BG monitoring). 15. Known hypersensitivity to any form of triamcinolone. 16. A history of sarcoidosis or amyloidosis. 17. Active malignant disease or a history of malignant disease within the past three years, excluding excised basal cell carcinoma, squamous cell carcinoma of the skin, or effectively controlled cervical cancer. 18. Known active or inactive systemic fungal infections, bacterial infections (including tuberculosis), viral infections or parasitic infections, or ocular herpes simplex. 19. Any infection requiring intravenous IV antibiotics within 4 weeks of screening, or an infection requiring oral antibiotics within 2 weeks of screening. 20. History of osteomyelitis. 21. A known or clinically suspected infection caused by human immunodeficiency virus (HIV) or hepatitis B or C virus. 22. Any clinically significant electrocardiogram (ECG) abnormality as determined by the principal investigator. 23. Subjects who, based on their medical history, require or are likely to require treatment with corticosteroids during the study period. 24. History of active Cushing's syndrome. 25. Active mental disorders, including psychosis (e.g., schizophrenia), bipolar disorder, uncontrolled anxiety disorder, and major depressive disorder. 26. Abuse of active substances (drugs or alcohol) within the past year, a history of chronic substance abuse, or a history of chronic substance abuse that the principal investigator determines is likely to recur during the study period. 27. Skin damage at the knee where the injection is administered. 28. Use of immunomodulatory drugs, immunosuppressant drugs, or chemotherapeutic agents within three years of screening. 29. The individual must have received a live vaccine or live attenuated vaccine within three months of the screening. 30. Use of any other investigational drug or device within 30 days of screening or within 5 half-lives (whichever is longer), or use of an investigational bioagent within 60 days of screening or within 5 half-lives (whichever is longer). 31. Any other clinically significant acute or chronic medical condition that, in the judgment of the principal investigator, could interfere with the use of IA corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), impair the safety of the subject, limit the ability to complete the study, and / or impair the purpose of the study. 32. The participant must have a positive pregnancy test at any given time of visit, and be breastfeeding or intending to become pregnant during the period from screening to the end of the study.

[0053] Injection administration procedure IA injections are administered by designated open-label injectors with considerable experience in administering IA injections and who are trained in the study administration procedure. The injector may select the knee position (e.g., extended or flexed), the injection approach (e.g., medial or lateral), and the local anesthetic (numbing agent) to be used (e.g., ethyl chloride or subcutaneous lidocaine; IA anesthetics are not permitted) based on standard treatment. After aspiration, 5 mL of reconstituted TA-ER or TA-IR (1 mL) and 5 mL of physiological saline (4 mL) are injected into the synovial space. The same needle used for the IA injection of the study drug may also be used for synovial aspiration, thereby enabling a single injection with syringe change. The injector uses a 21 gauge or larger needle for injection and fluid aspiration.

[0054] Research endpoints The primary endpoints of the study include the percentage of time spent exceeding 250 mg / dL (TAR) from baseline to 72 hours (days 0-3) for TA-IR and TA-ER, and the proportion of subjects who reached a TAR exceeding 250 mg / dL from baseline to 72 hours (days 0-3) for TA-IR and TA-ER. Secondary and exploratory endpoints include: (1) comparison of group differences in FBG levels at the median, 75th percentile, and 90th percentile levels during the study period (days 0-14) from baseline using AGP analysis for TA-IR and TA-ER; (2) median time to maximum hourly mean BG value from baseline to 72 hours (days 0-3) using Kaplan-Meier analysis for TA-IR and TA-ER; and (3) time from baseline to 0-24 hours (days 0-1) and 0-48 hours (days 0-1) for TA-IR and TA-ER. (1) Mean total change in DSC-R (Revised Diabetes Symptom Checklist) scores for psychological fatigue, psychological cognition, and hyperglycemia domains up to day 2, and for the period from 0 to 72 hours (days 0 to 3), (2) median of CGM-derived AGP analysis for TA-ER compared to TA-IR, comparison of BG study groups from baseline (-7 to day 0) to day 14 regarding the 75th and 90th percentile levels, (3) validated formula (Bergenstal) as follows: GMI (%) = 3.31 + 0.02392 × [mean glucose in mg / dL] (6) This includes a comparison of the study mean GMI for TA-ER to TA-IR, quantified using CGM-derived BG values ​​over the study period, as reported by et al. Diabetes Care. 2018 Nov; 41(11): 2275-2280), and the incidence of adverse events (TEAEs) and serious TEAEs (SAEs) occurring under treatment after baseline (days 0-14).

[0055] The percentage of time spent with a blood glucose level (BG) above 250 mg / dL from baseline to 72 hours (days 0-3): To calculate this endpoint, the mean hourly blood glucose is first calculated from each time point. Each time point is classified as either BG above or below 250 mg / dL. The number of hours with a BG above 250 mg / dL is totaled from baseline to 72 hours (days 0-3) and divided by the total number of hours during the same period within each subject. The obtained endpoint is analyzed using a linear model with fixed effects on the treatment group, along with covariates: mean pre-treatment BG value and the day the subject received the drug injection.

[0056] The proportion of subjects who reach a BG level exceeding 250 mg / dL within 72 hours (days 0-3) after baseline: To calculate this endpoint, the following binary variable is created for each subject: whether the BG level reaches a value exceeding 250 mg / dL within the first 72 hours after baseline. This endpoint is analyzed using a generalized linear model (i.e., a logistic regression model) with a binomial family and logit link function. This model includes the same fixed effects and covariates as the model described above.

[0057] Percentiles of Fasting Portable Glucose Profile (AGP): Fasting AGP is calculated and analyzed as follows: BG levels collected in the last hour before the first meal of the day are flagged and retained in the dataset as FBG reads. Mean BG levels are calculated daily for 30-minute blocks (7:00-7:30, 7:31-7:59) throughout the post-baseline period (i.e., days 0-14). The obtained fasting AGP is analyzed using a mixed quantile regression model for repeated measures (MQRMRM) with fixed effects for treatment group, day, and group-by-day interaction, along with mean pre-treatment BG values ​​and the time of day the subject received drug injection as covariates. This model includes subject random effects. This model estimates the fixed effects of fasting AGP on the 50th (i.e., median), 75th, and 90th percentiles. (The analysis assumes the use of the R package, as mixed-effects quantile regression is not available in SAS.)

[0058] The median time to the maximum hourly mean BG value during the first 1-72 hours (days 0-3): This endpoint, the time to this event, is analyzed using the Kaplan-Meier estimator with the time to reach maximum BG as the outcome and the treatment group as the stratification.

[0059] For all analyses, baseline covariates not mentioned above (e.g., baseline age, sex, BMI, weight) may be considered for inclusion in the model.

[0060] (Example 2) This example summarizes the analysis of results from a randomized, parallel-group, double-blind phase 2 study and clinical research comparing the effects of extended-release (TA-ER) and immediate-release (TA-IR) triamcinolone acetonide on blood glucose (BG) in patients with osteoarthritis of the knee and type 2 diabetes mellitus.

[0061] research design Eligible participants are at least 40 years of age and have symptomatic knee osteoarthritis and type 2 diabetes mellitus managed with either an injectable or oral antidiabetic agent, or both. Participants should have been receiving a stable dose of the injectable or oral agent for at least one month prior to study screening and should have an HbA1c level of ≤9.0% at screening. Approximately 120 participants should be randomized to one of two treatment groups, receiving either TA-ER 32 mg or TA-IR 40 mg. Each participant's BG level should be collected and evaluated over a total of three weeks, spanning one week before and two weeks after injection.

[0062] Following the screening visit, the subject's BG level should be measured using a CGM device for up to one week before injection and two weeks after injection. Subjects should be blinded to the treatment assignment but not to glucose readings. Subjects should use a 6-point self-monitoring BG (SMBG) profile measured using a downloadable blood glucose meter, starting the day before administration and continuing until 72 hours after administration.

[0063] Treatment arm The treatment arm includes the following: A 32 mg extended-release formulation of triamcinolone acetonide in 75:25 PLGA (poly(lactic acid-co-glycolic acid)) microspheres, administered as a 5 mL IA knee injection. A 40 mg immediate-release formulation of triamcinolone acetonide injection suspension, administered as a 1 mL 1A knee injection.

[0064] Inclusion Criteria During the screening period (unless otherwise specified below), each participant must meet all of the following criteria to be enrolled in this study: 1. A man or woman who is at least 40 years old. 2. Type 2 diabetes mellitus for at least one year prior to screening. 3. The patient has been currently treated with a stable dose of an injectable (non-insulin) and / or oral antidiabetic agent for at least one month prior to screening. 4. HbA1c level of 9.0% or less at the time of screening. 5.50mL / min / 1.73m 2 The above is the estimated glomerular filtration rate (eGFR). Triglycerides less than 6,500 mg / dL. 7. Painful symptoms associated with knee osteoarthritis for at least six months prior to screening. 8. Currently meets the revised American College of Rheumatology criteria (clinical and radiological) for OA (Altman et al, 1986): a. Knee pain b. At least one of the following: Stiffness lasting less than 30 minutes hair twisting sound c.steophyte. 9. Originating knee pain (reported by the subject) on most days (more than 15 days) over the past month. 10. Kergren-Lawrence grade 2 or 3 on knee X-ray.

[0065] Exclusion criteria Participants who meet any of the following criteria (except as specified below during the screening period) will be excluded from this study: 1. Arthritis associated with Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease. 2. A medical history of the initial knee joint infection. 3. Clinical signs and symptoms of an active knee infection or crystalline disease of the knee at the time of screening within one month prior to the screening. 4. The presence of surgical hardware or other foreign objects in the knee at the time of the injury. 5. Joint instability within 12 months of screening (e.g., anterior cruciate ligament rupture). 6. IA corticosteroid (investigative or commercially available) in any joint within 3 months of screening. 7. IA hyaluronic acid (in clinical trials or commercially available) in the knee at the time of screening within 6 months prior to the screening. 8. IV or IM corticosteroid (investigative or marketed) within 3 months of screening. 9. Oral corticosteroids (in clinical trials or commercially available) within one month of screening. 10. Inhalation, intranasal, or topical corticosteroids (investigative or commercially available) within two weeks of screening. 11. Any other IA investigational device / drug / biologic with a half-life of 6 months or 5 months (whichever is longer) of the screening period. 12. Arthroscopic or open surgery of the knee at the time of the initial injury within 12 months of the screening. 13. Planning / scheduling of any initial knee surgery or any other surgery during the study period. 14. Use of acetaminophen or acetaminophen-containing products from screening to day 14 (completion of post-treatment BG monitoring). Subjects ingesting coumadin with an INR of 15.5 or higher. 16. Known hypersensitivity to any form of triamcinolone. 17. A history of sarcoidosis or amyloidosis. 18. Active malignant disease or a history of malignant disease within the past three years, excluding excised basal cell carcinoma, squamous cell carcinoma of the skin, or effectively controlled cervical cancer. 19. Known active or inactive systemic fungal infections, bacterial infections (including tuberculosis), viral infections or parasitic infections, or ocular herpes simplex. 20. Any infection requiring intravenous IV antibiotics within 4 weeks of screening, or an infection requiring oral antibiotics within 2 weeks of screening. 21. History of osteomyelitis. 22. A known or clinically suspected infection caused by human immunodeficiency virus (HIV) or hepatitis B or C virus. 23. Any clinically significant cardiac abnormality or clinically significant abnormal electrocardiogram (ECG) reading that interferes with IA steroid treatment as determined by the principal investigator. 24. Subjects who, based on their medical history, require or are likely to require treatment with corticosteroids during the study period. 25. History of active Cushing's syndrome. 26. Abuse of active substances (drugs or alcohol) within the past year, a history of chronic substance abuse, or a history of chronic substance abuse that the principal investigator determines is likely to recur during the study period. 27. Skin damage at the knee where the injection is administered. 28. Use of immunomodulatory drugs, immunosuppressant drugs, or chemotherapeutic agents within two years of screening. 29. The individual must have received a live vaccine or live attenuated vaccine within three months of the screening. 30. Any other clinically significant acute or chronic mental and / or medical condition that, in the judgment of the principal investigator, could interfere with the use of IA corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), impair the safety of the subject, limit the subject's ability to complete the study, and / or impair the purpose of the study. 31. The patient must have a positive pregnancy test at any given time of visit, and be breastfeeding or intending to become pregnant during the period from screening to the end of the study.

[0066] Injection administration procedure IA injections are administered by designated open-label injectors with considerable experience in IA injection administration and trained in the study administration procedure. The injector may select the knee position (e.g., extended or flexed), injection approach (e.g., medial or lateral), and local anesthetic to be used (e.g., ethyl chloride or subcutaneous lidocaine; IA anesthetics are not permitted) based on standard treatment. After aspiration, 5 mL of reconstituted TA-ER or TA-IR (1 mL) and 5 mL of saline (4 mL) are injected into the synovial space. The same needle used for the IA injection of the study drug may also be used for synovial aspiration, thereby enabling a single injection with syringe change. The injector uses a 21-gauge or larger needle for injection and fluid aspiration. Injections into the knee joint are performed using ultrasound guidance.

[0067] Research endpoints The primary endpoint of the study includes the number of subjects who spend more than 25% of their time in a TAR exceeding 180 mg / dL from baseline to post-baseline (0-3 days) for TA-IR compared to TA-ER. Secondary and exploratory endpoints included: (1) the number of subjects with insulin levels exceeding 180 mg / dL from baseline to 72 hours and the percentage of time spent comparing TA-ER and TA-IR; (2) the number of subjects with peak levels of 250 mg / dL or higher from baseline to 72 hours comparing TA-ER and TA-IR; (3) the number of subjects whose insulin consumption increased from baseline to 2 weeks post-administration by comparing the effect of TA-ER versus TA-IR on BG; (4) the area under the curve (AUC) (day 30) for cortisol levels after ACTH stimulation from baseline to the end of the study comparing TA-ER versus TA-IR; (5) the group difference in pre-breakfast FBG levels (confirmed by a blood glucose meter) for TA-ER versus TA-IR; and (6) the validated formula for GMI (%) as follows: GMI (%) = 3.31 + 0.02392 × [mean glucose in mg / dL] (Bergenstal et al. Diabetes Care. 2018-Nov; 41(11): (2275-2280) The study included: (6) a comparison of the mean study GMI for TA-ER over the study period from 1 to 15 days after baseline, (7) the mean weekly and total consumption of emergency medications for TA-ER over 30 days compared to TA-IR, (8) the AUC of the change from baseline in the mean worst daily knee pain score at week 4 for TA-ER compared to TA-IR, (9) the mean total change in DSC-R scores in the psychological fatigue, psychological cognition and hyperglycemia domains from baseline to 0-24 hours (days 1-2), 0-48 hours (days 1-3), and 0-72 hours (days 1-4) for TA-ER compared to TA-IR, and (10) the incidence of treatment-induced adverse events (TEAEs) and serious TEAEs (SAEs) from baseline to day 30.

[0068] The number of subjects who spend more than 25% of their time with a TAR exceeding 180 mg / dL from baseline to post-baseline (0-3 days): To calculate this endpoint, first, the mean hourly mean CGM level is calculated by taking the average of the 5-minute CGM levels for each 72 hours after baseline. Next, the number of hours with an hourly mean level exceeding 180 mg / dL is counted and divided by the number of valid hours (percentage of time exceeding 180). Finally, the number of subjects with a percentage of time exceeding 180 that exceeds 25% is counted. This endpoint is analyzed using a generalized linear model (i.e., a logistic regression model) with a binomial family distribution and logit link function, with the number of subjects in each treatment condition as the denominator. This model includes the fixed effects of the treatment condition and relevant covariates, including HbA1c.

[0069] The number of subjects with a blood alcohol content exceeding 180 mg / dL from baseline to 72 hours (0–3 days), and the percentage of time spent with this excess: This endpoint will be analyzed using a generalized linear model (GLM) with a beta family distribution and logit link function.

[0070] The number of peaks ≥250 mg / dL per subject from baseline to 72 hours, comparing TA-ER and TA-IR: To calculate this endpoint, the number of peaks for each subject is calculated by counting the number of hourly mean CGM levels above 250 mg / dL that are around the level below 250. This endpoint is analyzed using GLM with a Poisson family distribution and a log-link function.

[0071] The number of subjects whose insulin consumption increased from baseline to 2 weeks post-treatment by comparing the effect of TA-ER versus TA-IR on BG: This endpoint will be analyzed as follows: (1) calculate the change in insulin consumption from baseline to day 14, (2) flag subjects who consumed more insulin on day 15, and (3) analyze the binary endpoint using Fisher's exact method.

[0072] AUC (day 30) of cortisol levels after ACTH stimulation testing from baseline to end of study, comparing TA-ER vs. TA-IR: This endpoint was analyzed using a linear model and then logarithmically or squarely rooted to approximate a normal distribution.

[0073] The weekly mean change from baseline in the mean daily pain score for TA-ER compared to TA-IR: This endpoint is calculated by subtracting the baseline value from the following week. The endpoint is analyzed by submitting to a longitudinal mixed model with random effects and fixed time effects for the target IDS.

[0074] Mean total change in DSC-R scores in the domains of psychological fatigue, psychological cognition, and hyperglycemia: Each of these endpoints will be analyzed using a linear model with appropriately transformed endpoints as needed.

[0075] The incidence of therapeutic adverse events (TEAEs) and serious therapeutic events (SAEs) occurring under treatment from baseline to day 30: This endpoint will be analyzed using GLM with a Poisson distribution and log link function.

[0076] For all analyses, baseline covariates not mentioned above (e.g., baseline age, sex, BMI, weight) may be considered for inclusion in the model. TA-ER treatment is expected to satisfy one or more of the endpoints described herein compared to TA-IR treatment.

Claims

1. A method for treating pain in osteoarthritis of the knee in patients with diabetes, wherein the method is: A step of identifying or selecting subjects with diabetes mellitus (DM) who are at risk of developing hyperglycemia caused by intra-articular injection of corticosteroids, The steps include determining the baseline blood glucose level of the subject or obtaining information regarding the baseline blood glucose level of the subject, The procedure involves administering approximately 32 mg of an extended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra-articular injection. Includes, The extended-release formulation of TA is an extended-release formulation of TA containing poly(lactic acid-co-glycol) acid (PLGA) microspheres in a molar ratio of 75:

25. A method for reducing the percentage of time during a certain period after administration when administering the extended-release formulation of TA compared with administering 40 mg of the immediate-release formulation of TA, by reducing the duration of time when the blood glucose level exceeds 180 mg / dL.

2. The method according to claim 1, wherein the percentage of time spent with a blood glucose level exceeding 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

3. The method according to claim 1 or 2, wherein the subject spends approximately 25% or less of the time during a certain period after administration at a blood glucose level of 180 mg / dL or higher.

4. The method according to any one of claims 1 to 3, wherein the administration of the extended-release formulation of TA further reduces the possibility that the target blood glucose level will exceed 180 mg / dL during a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

5. The method according to claim 4, wherein the possibility of the target blood glucose level exceeding 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

6. The method according to any one of claims 1 to 5, wherein the administration of the extended-release formulation of TA also increases the time to reach a blood glucose level of 180 mg / dL within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

7. The method according to claim 6, wherein the time to reach the blood glucose level of 180 mg / dL is increased by at least about 25%, 50%, 75%, 1x, 1.5x, 2x, 2.5x, 3x, 4x, or 5x during a certain period after administration.

8. The method according to any one of claims 1 to 7, wherein administration of the extended-release formulation of TA reduces the percentage of time during which blood glucose levels exceed 250 mg / dL during a certain period after administration, compared to administration of 40 mg of the immediate-release formulation of TA.

9. The method according to claim 8, wherein the percentage of time spent with a blood glucose level exceeding 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

10. The method according to claim 8 or 9, wherein the administration of the extended-release formulation of TA further reduces the likelihood that the target blood glucose level will exceed 250 mg / dL during a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

11. The method according to claim 10, wherein the possibility of the target blood glucose level exceeding 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

12. The method according to any one of claims 8 to 11, wherein the administration of the extended-release formulation of TA also increases the time to reach a blood glucose level of 250 mg / dL within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

13. The method according to claim 12, wherein the time to reach the blood glucose level of 250 mg / dL is increased by at least about 25%, 50%, 75%, 1x, 1.5x, 2x, 2.5x, 3x, 4x, or 5x during a certain period after administration.

14. A method for treating pain in osteoarthritis of the knee in patients with diabetes, wherein the method is: A step of identifying or selecting subjects with diabetes mellitus who are at risk of developing hyperglycemia caused by intra-articular injection of corticosteroids, The steps include determining the baseline blood glucose level of the subject or obtaining information regarding the baseline blood glucose level of the subject, The procedure involves administering approximately 32 mg of an extended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra-articular injection. Includes, The extended-release formulation of TA is an extended-release formulation of TA containing poly(lactic acid-co-glycol) acid (PLGA) microspheres in a molar ratio of 75:

25. A method for reducing the likelihood that the administration of the extended-release formulation of TA will result in the target blood glucose level exceeding 180 mg / dL within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

15. The method according to claim 14, wherein the possibility of the target blood glucose level exceeding 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

16. The method according to claim 14 or 15, wherein administration of the extended-release formulation of TA also reduces the percentage of time during which blood glucose levels exceed 180 mg / dL during a certain period after administration, compared to administration of 40 mg of the immediate-release formulation of TA.

17. The method according to claim 16, wherein the percentage of time spent with a blood glucose level exceeding 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

18. The method according to claim 16 or 17, wherein the administration of the extended-release formulation of TA also increases the time to reach a blood glucose level of 180 mg / dL within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

19. The method according to claim 18, wherein the time to reach the blood glucose level of 180 mg / dL is increased by at least about 25%, 50%, 75%, 1x, 1.5x, 2x, 2.5x, 3x, 4x, or 5x during a certain period after administration.

20. The method according to any one of claims 14 to 19, wherein the administration of the extended-release formulation of TA reduces the likelihood that the target blood glucose level will exceed 250 mg / dL during a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

21. The method according to claim 20, wherein the possibility of the target blood glucose level exceeding 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

22. The method according to claim 20 or 21, wherein administration of the extended-release formulation of TA also reduces the percentage of time during which blood glucose levels exceed 250 mg / dL during a certain period after administration, compared to administration of 40 mg of the immediate-release formulation of TA.

23. The method according to claim 22, wherein the percentage of time spent with a blood glucose level exceeding 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

24. The method according to any one of claims 20 to 23, wherein the administration of the extended-release formulation of TA also increases the time to reach a blood glucose level of 250 mg / dL within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

25. The method according to claim 24, wherein the time to reach the blood glucose level of 250 mg / dL is increased by at least about 25%, 50%, 75%, 1x, 1.5x, 2x, 2.5x, 3x, 4x, or 5x during a certain period after administration.

26. The method according to any one of claims 1 to 25, wherein the administration of the extended-release formulation of TA increases the time to reach the maximum blood glucose level within a certain period after administration, compared to the administration of 40 mg of the immediate-release formulation of TA.

27. The method according to claim 26, wherein the time to reach the maximum blood glucose level is increased by at least about 25%, 50%, 75%, 1x, 1.5x, 2x, or 2.5x during a certain period after administration.

28. The method according to any one of claims 1 to 27, wherein the administration of the extended-release formulation of TA increases the percentage of time spent within the target blood glucose range of 70 mg / dL or more and 180 mg / dL or less during a certain period after administration, compared with the administration of 40 mg of the immediate-release formulation of TA.

29. The method according to claim 28, wherein the percentage of time spent within the target blood glucose range is increased by at least about 10%, 20%, 30%, 40%, or 50% during a certain period after administration.

30. The method according to any one of claims 1 to 29, wherein the insulin consumption of the target after administration of the extended-release formulation of TA is less than the insulin consumption after administration of 40 mg of the immediate-release formulation of TA for up to two weeks.

31. The method according to any one of claims 1 to 30, wherein the average daily knee pain intensity score of the subject during a certain period after administration of the extended-release formulation of TA is smaller than the average daily knee pain intensity score during a certain period after administration of the immediate-release formulation of TA 40 mg.

32. The method according to any one of claims 1 to 31, further comprising the step of continuously monitoring the blood glucose level of the target after injection to determine the blood glucose level of the target during a certain period after administration.

33. The method according to claim 32, wherein the continuous monitoring is performed using a continuous glucose monitoring (CGM) device.

34. The method according to any one of claims 1 to 33, wherein the period after administration is approximately or at least approximately 24 hours, approximately 48 hours, or approximately 72 hours.

35. The method according to any one of claims 1 to 34, wherein the immediate-release formulation of TA is a 40 mg / mL injectable suspension administered by intra-articular injection of 1 mL.

36. The method according to any one of claims 1 to 35, wherein the subject having diabetes mellitus is managed with one or more antidiabetic agents prior to the treatment.

37. The method according to claim 36, further comprising the step of adjusting the dosage of one or more antidiabetic agents when the target blood glucose level exceeds the target blood glucose range of 70 mg / dL or more and 180 mg / dL or less.

38. The method according to any one of claims 1 to 37, wherein the subject had type 1 DM for at least one year prior to the treatment.

39. The method according to any one of claims 1 to 37, wherein the subject had type 2 DM for at least one year prior to the treatment.

40. The method according to any one of claims 1 to 39, wherein the subject having DM has a hemoglobin A1c (HbA1c) level of 9.0% or less before commencing the treatment.

41. The method according to claim 40, wherein the subject having DM has a hemoglobin A1c (HbA1c) level of 6.5% or more and less than 9.0% before the commencement of the treatment.

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