Injectable composition comprising tadalafil or pharmaceutically acceptable salts thereof

Abstract

The present disclosure relates to an injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent. The injectable composition according to the present disclosure has the advantages of achieving a constant level of drug blood concentration over a long period of time, thereby reducing the number of drug administration, having excellent long-term safety due to absence of local tolerance and minimal side effects due to absence of initial rapid drug release, and providing high formulation stability.

Description

INJECTABLE COMPOSITION COMPRISING TADALAFIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

[0001] The present disclosure relates to an injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent.

[0002] Benign prostatic hyperplasia (BPH) is an abnormally enlarged prostate gland that commonly affects men over the age of 40. The prostate gland is situated near the bladder and surrounds the urethra. With the development of prostatic hyperplasia, the prostate gland increases in size and exerts pressure on the bladder and urethra, leading to impaired bladder function and obstruction of urinary flow. This may result in decreased urine volume and flow, difficulty passing urine, and complications such as urinary incontinence and urethral obstruction. According to the Korea Centers for Disease Control and Prevention, BPH is a very common disease that begins gradually after the age of 40, affects about 60% to 70% of men in their 60s, and almost all men in their 70s, and is generally considered a normal aspect of the aging process. Therefore, the treatment of prostatic hyperplasia, a chronic age-related disease, aims to alleviate the patient's symptoms and prevent potential complications. Common drug treatments include alpha-blockers, such as tamsulosin and doxazosin, and 5α-reductase inhibitors (5-ARIs), such as finasteride and dutasteride. However, these medications may cause significant side effects, such as hypotension, or may be ineffective.

[0003] Meanwhile, erectile dysfunction is the inability to achieve or maintain an erection sufficient for sexual activity, and is generally defined as erectile dysfunction when the condition persists for more than three months. Erectile dysfunction is a condition in which the corpora cavernosa of the penis do not expand enough to sufficiently constrict the veins and prevent penile blood flow outflow. This may be caused by a lack of cyclic guanosine monophosphate (cGMP), a vasodilator that maintains an erection by relaxing smooth muscle to increase blood flow to the corpora cavernosa of the penis, or by a lack of blood vessel response to cGMP. Without sufficient expansion of the penile corpora cavernosa, an erection cannot be maintained because blood flow escapes through the non-contracted veins. Phosphodiesterase type 5 (PDE5) is responsible for triggering the breakdown of cGMP, which is necessary to maintain a normal erection, and thus terminates an erection.

[0004] Tadalafil is a PDE5 inhibitor, which is used to treat erectile dysfunction by inhibiting PDE5, an enzyme that decomposes cGMP present in smooth muscle, and is also used to treat prostatic hyperplasia by relaxing the muscles of the bladder and prostate and improving lower urinary tract symptoms. Tadalafil is indicated for the treatment of erectile dysfunction and benign prostatic hyperplasia with oral therapy at a dose of 5 mg once a day. However, due to the nature of chronic diseases, long-term continuous drug administration is required to effectively improve symptoms of benign prostatic hyperplasia and erectile dysfunction.

[0005] Korean Registered Patent No. 10-2244717 discloses a self-nanoemulsifying solid composition for drug delivery containing tadalafil. Specifically, the composition contains oil, a surfactant, and a co-surfactant in addition to tadalafil. Meanwhile, the above patent relates to a composition for oral administration of tadalafil, which has only the purpose and effect of improving the solubility, dissolution rate, and bioavailability of tadalafil, and is not suitable at all for an injectable formulation enabling sustained drug efficacy over a long period since the blood drug concentration of tadalafil completely dissipates after one day of administration.

[0006] In addition, Korean Registered Patent No. 10-2646431 discloses a solid formulation containing tadalafil and an additive, and discloses that the additive may include sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid ester, etc. However, the patent relates to a solid formulation of tadalafil, and has only the purpose and effect of improving the productivity, uniformity, and dissolution rate of tadalafil, and is not suitable for use in injectable formulations enabling sustained drug efficacy over a long period.

[0007] An object of the present disclosure is to provide an injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent. Specifically, another object of the present disclosure is to provide an injectable composition comprising tadalafil that enables a sustained release of the drug over a long period of time, thereby increasing convenience by reducing the number of drug administrations, reducing side effects due to the absence of an initial rapid drug release, and providing high safety and formulation stability.

[0008] In one general aspect, the present disclosure provides a novel injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent.

[0009] The injectable composition of the present disclosure is a depot injectable composition in which, upon administration into the human body, the solvent rapidly dissipates and the lipid forms a depot together with the drug at the administration site, resulting in sustained release of the drug over an extended period.

[0010] As used herein, tadalafil is a compound represented by the following Chemical Formula 1, and refers to a selective and reversible inhibitor of phosphodiesterase type 5 (PDE5), an enzyme that decomposes cGMP. Specifically, tadalafil inhibits PDE5, an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP) when sexual stimulation causes local release of nitric oxide and leads to the synthesis of cGMP. The resulting increase in cGMP in the corpora cavernosa of the penis induces relaxation of smooth muscles and facilitates blood flow into the penile tissue, thereby causing an erection. The PDE5 inhibitory effect on the increase of cGMP in the corpora cavernosa of the penis causes the blood vessels to relax and increases blood perfusion, thereby relieving the symptoms of benign prostatic hyperplasia Tadalafil, which exhibits these effects, is currently available on the market as a once-daily oral therapeutic agent for the treatment of benign prostatic hyperplasia and erectile dysfunction.

[0011] [Chemical Formula 1]

[0012]

[0013]

[0014] In the present disclosure, the tadalafil may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. As used herein, the term “pharmaceutically acceptable salt” of tadalafil refers to any organic or inorganic addition salt of tadalafil at a concentration having a relatively non-toxic and harmless effective effect on patients in which side effects caused by these salts do not reduce the beneficial efficacy of tadalafil.

[0015] The acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Here, an equimolar amount of the compound and an acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.

[0016] During the process, as the free acid, organic acids and inorganic acids may be used, in which the inorganic acid may include hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid, and the like, and the organic acid may include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, and the like.

[0017] According to an embodiment of the present disclosure, the tadalafil or a pharmaceutically acceptable salt thereof may be contained in an amount of 30 to 600 mg per volume (mL) of the injectable composition.

[0018] Preferably, the tadalafil or a pharmaceutically acceptable salt thereof according to the present disclosure may be contained in an amount of 30 to 300 mg per volume (mL) of the injectable composition.

[0019] In addition, the tadalafil or a pharmaceutically acceptable salt thereof according to the present disclosure may be contained in an amount of 1 to 50 wt% based on the total weight of the injectable composition.

[0020] Preferably, the tadalafil or a pharmaceutically acceptable salt thereof according to the present disclosure may be contained in an amount of 1 to 30 wt% based on the total weight of the injectable composition.

[0021] In the present disclosure, when administered to the human body, the lipid remains at the administration site together with tadalafil, and is gradually absorbed into the body over time, affecting the release and absorption of tadalafil. Specifically, the lipid is a biodegradable lipid that forms a depot at the administration site together with tadalafil to slowly release tadalafil. As used herein, the term “depot” means any system that delays drug release through interaction between body fluids, lipids, and drugs, and the formation of the depot serves to sustain the therapeutic efficacy of the drug in the body over an extended duration.

[0022] According to an embodiment of the present disclosure, the lipid may be any one selected from the group consisting of castor oil, safflower oil, sesame oil, olive oil, peanut oil, almond oil, camellia oil, corn oil, cottonseed oil, soybean oil, medium chain triglycerides, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0023] The lipid included in the injectable composition of the present disclosure may be used as such or in the form of pharmaceutically acceptable salts thereof. In the present disclosure, the pharmaceutically acceptable salt of the lipid means any arbitrary organic or inorganic acid addition salt at a concentration having a relatively non-toxic and harmless effective effect on patients in which side effects caused by these salts do not reduce the beneficial efficacy of the pharmacologically active ingredient. Specifically, a method for forming the salt and the type of acid that is usable are the same as those described above for the pharmaceutically acceptable salt of tadalafil.

[0024] Preferably, the lipid may be contained in an amount of 5 to 50 wt% based on the total weight of the injectable composition.

[0025] In addition, preferably, the lipid in the injectable composition of the present disclosure may be castor oil, a pharmaceutically acceptable salt thereof, or a mixture thereof.

[0026] More preferably, the injectable composition of the present disclosure may comprise castor oil, a pharmaceutically acceptable salt thereof, or a mixture thereof as a lipid, and the lipid may be contained in an amount of 5 to 50 wt% based on the total weight of the composition.

[0027] In the present disclosure, the co-solvent is added to solubilize tadalafil, facilitate preparation, and reduces the viscosity of the composition, providing convenience during administration.

[0028] According to an embodiment of the present disclosure, the co-solvent may be any one selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, benzyl alcohol, dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, and mixtures thereof.

[0029] Preferably, the co-solvent of the present disclosure may be contained in an amount of 40 to 90 wt% based on the total weight of the injectable composition.

[0030] In addition, preferably, the co-solvent in the injectable composition of the present disclosure may be N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, dimethylacetamide, ethanol or a mixture thereof, and may be contained in an amount of 40 to 90 wt% based on the total weight of the composition.

[0031] In addition, preferably, the co-solvent in the injectable composition of the present disclosure may be N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, dimethylacetamide or a mixture thereof, and may be contained in an amount of 40 to 90 wt% based on the total weight of the composition.

[0032] The injectable composition of the present disclosure may further comprise a pharmaceutically acceptable additive, in addition to tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent, within a range that does not impair the effectiveness of the present disclosure.

[0033] The pharmaceutically acceptable additive may include, without limitation, pH adjusting agents, isotonic agents, surfactants, stabilizers, preservatives, chelating agents, buffering agents, water for injection, or combinations thereof commonly used in the art.

[0034] The pH adjusting agent serves to adjust the pH of the composition and may include both acidic and basic substances. For example, the pH adjusting agent may include at least one from the group consisting of hydrochloric acid, sodium hydroxide, citric acid, acetic acid, phosphoric acid, gluconic acid, ascorbic acid, and succinic acid.

[0035] The pH of the composition according to the present disclosure may be adjusted to a range suitable for injections, etc., thereby implementing a pH range acceptable for injection into the body, and achieving excellent solution stability since the formation of precipitates is low during long-term storage.

[0036] The isotonic agent may include sugars, sugar alcohols, and salts. For example, the isotonic agent may include glucose, glycerin, sodium chloride, calcium chloride, sodium sulfate, propylene glycol, polyethylene glycol, dextrose, hydroxypropyl betadex, mannitol, potassium chloride, dextran, Ficoll, gelatin, hydroxyethyl starch, and the like.

[0037] The surfactant may include an ionic, nonionic, and / or amphoteric surfactant. For example, the nonionic surfactant may include polyoxyethylene sorbitan fatty acid esters and polyoxyethylene-polyoxypropylene block copolymers, etc.

[0038] The stabilizer may include, for example, cholesterol, β-cholesterol, sitosterol, ergosterol, stigmasterol, stigmasterol acetate, lanosterol, and combinations thereof, etc.

[0039] The preservative may include antimicrobial agents commonly used in the pharmaceutical field. The preservative may include glycerin, phenol, benzalkonium chloride, benzethonium chloride, acacia, albumin, alcohol, alginic acid, ascorbyl palmitate, aspartame, boric acid, citric acid, pentetic acid, sodium acetate, sorbic acid, chlorobutanol, o-cresol, m-cresol, ρ-cresol, chlorocresol, benzalkonium chloride, phenylmercuric acid nitrate, thimerosal, benzoic acid, cholesterol, etc.

[0040] The chelating agent may comprise ethylenediaminetetraacetic acid (EDTA), butylenediaminetetraacetic acid, cyclohexane-1,2-diaminetetraacetic acid (CyDTA), diethylenetriaminepentaacetic acid (DETPA), ethylenediaminetetrapropionic acid, (hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), N,N,N',N'-ethylenediaminetetra(methylenephosphonic)acid (EDTMP), triethylenetetraminehexaacetic acid (TTHA), 1,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid (DHPTA), methyliminodiacetic acid, propylenediaminetetraacetic acid, 1,5,9-triazacyclododecane-N,N',N''-tris(methylenephosphonic acid)(DOTRP), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid)(DOTP), nitrilotris(methylene)triphosphonic acid, diethylenetriaminepenta(methylenephosphonic acid)(DETAP), aminotri(methylenephosphonic acid), 1-hydroxyethylene-1,1-diphosphonic acid, bis(hexamethylene)triaminephosphonic acid, 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid)(NOTP), 2-phosphonobutane-1,2,4-tricarbonylic acid, nitrilotriacetic acid (NTA), citric acid, fumaric acid, malic acid, maltol, tartaric acid, gluconic acid, glyceric acid, oxalic acid, phthalic acid, maleic acid, mandelic acid, malonic acid, lactic acid, salicylic acid, methyl salicylate, 5-salicylic acid sulfate, gallic acid, propyl gallate, pyrogallol, 8-hydroxyquinoline, cysteine, etc.

[0041] The buffering agent may include disodium phosphate, citric acid, sodium citrate hydrate, potassium citrate, acetic acid, sodium acetate, sodium carbonate, calcium carbonate, tricalcium phosphate, calcium lactate, glycine, maleic acid, malic acid, sodium glutamate, monosodium glutamate, sodium lactate, sodium phosphate, and mixtures thereof, etc.

[0042] The water for injection is not particularly limited and may be used as water for injection generally used for dissolving, suspending or emulsifying a composition, and preferably, may be saline solution, glucose water for injection, xylitol water for injection, D-mannitol water for injection, fructose water for injection, dextran 40 water for injection, dextran 70 water for injection, amino acid water for injection, Ringer's solution, or lactated Ringer's solution.

[0043] According to an embodiment of the present disclosure, the injectable composition may be used as a therapeutic agent for benign prostatic hyperplasia or erectile dysfunction.

[0044] In addition, the injectable composition of the present disclosure may further include any active ingredient that exhibits a significant effect in alleviating the symptoms of benign prostatic hyperplasia or erectile dysfunction, such as an alpha blocker, a 5-ARI, and a PDE5 inhibitor, etc.

[0045] The injectable composition of the present disclosure may be prepared in various formulations.

[0046] Preferably, the injectable composition of the present disclosure may be a liquid preparation.

[0047] Preferably, the injectable composition of the present disclosure may be administered by intramuscular injection, subcutaneous injection, or intradermal injection.

[0048] The injectable composition of the present disclosure may be simply prepared by dissolving tadalafil or a pharmaceutically acceptable salt thereof in a lipid and a co-solvent, and may be administered by injection into the human body.

[0049] The single effective dosage of the injectable composition of the present disclosure may be appropriately changed depending on the patient's age, body weight, gender, dosage form, health condition, or disease severity, and is not specifically limited thereto in the present disclosure. However, for adults, the dosage may be 1 mg to 1000 mg, and may be administered in divided doses once or several times per month. In the present disclosure, administering once a month means administering once every 28 to 31 days.

[0050] Preferably, the injectable composition of the present disclosure may be administered once every 28 to 45 days.

[0051] More preferably, the injectable composition of the present disclosure may be administered once a month.

[0052] The injectable composition of the present disclosure may maintain the blood concentration of tadalafil at an effective concentration level for at least 1 week, 14 days, or 28 days after the time of administration, and the efficacy may remain for up to 45 days. Therefore, the injectable composition of the present disclosure is suitable as a long-acting sustained-release injection.

[0053] The injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent of the present disclosure has the advantages of achieving a constant level of drug blood concentration over a long period of time, thereby reducing the number of drug administration, having excellent long-term safety due to absence of local tolerance and minimal side effects due to absence of initial rapid drug release, and providing high formulation stability.

[0054] FIG. 1 shows a blood concentration of tadalafil measured after administering an injectable composition of the present disclosure to rats.

[0055] FIG. 2 shows a blood concentration of tadalafil measured after administering an injectable composition of the present disclosure to rats.

[0056] FIG. 3 shows a blood concentration of tadalafil measured after administering the injectable composition containing castor oil or tocopherol as a lipid to rats.

[0057] FIG. 4 shows a dissolution rate of the injectable composition containing dutasteride as an active ingredient.

[0058] FIG. 5 shows the results of a local tolerance test conducted after administering the injectable composition of the present disclosure to rats.

[0059] Hereinafter, the present disclosure will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are only presented as examples of the present disclosure, and the scope of the present disclosure is not limited only to these Examples.

[0060] The additives used in the present disclosure were pharmacopoeia-grade excipients and reagents purchased from Aldrich and Croda.

[0061] Examples 1 to 12: Preparation of injectable compositions of the present disclosure

[0062] Each injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent of the present disclosure was prepared according to the specific ingredients and contents described in Table 1 below.

[0063] Specifically, the active ingredient tadalafil was mixed with a co-solvent (N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, dimethylacetamide or a combination thereof), and dissolved for about 30 to 60 minutes using a stirrer at room temperature (25 ℃) under conditions of about 1,000 to 3,000 rpm. Then, lipid (castor oil) was added to the prepared solution, and dissolved for about 5 to 30 minutes under conditions of about 1,000 to 3,000 rpm, thereby preparing each composition of Examples 1 to 12 in the solution phase, respectively.

[0064] [Table 1]

[0065]

[0066] Examples 13 to 20: Preparation of injectable compositions of the present disclosure

[0067] Each injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent of the present disclosure was prepared according to the specific ingredients and contents described in Table 2 below.

[0068] Specifically, the active ingredient tadalafil was mixed with a co-solvent (N-methyl-2-pyrrolidone, ethanol or a combination thereof), and dissolved for about 30 to 60 minutes using a stirrer at room temperature (25 ℃) under conditions of about 1,000 to 3,000 rpm. Then, lipid was added to the prepared solution, and dissolved for about 5 to 30 minutes under conditions of about 1,000 to 3,000 rpm, thereby preparing each composition of Examples 13 to 20 in the solution phase, respectively.

[0069] [Table 2]

[0070]

[0071] Comparative Examples 1 and 2: Preparation of injectable compositions containing tocopherol

[0072] The compositions of Comparative Examples 1 and 2 were prepared in the same manner as the compositions of Examples 1 to 12, except that tocopherol was used as a lipid, and the specific ingredients and contents used are listed in Table 3 below.

[0073] [Table 3]

[0074]

[0075]

[0076] Comparative Examples 3 and 4: Preparation of injectable compositions containing dutasteride

[0077] The compositions of Comparative Examples 3 and 4 were prepared in the same manner as the compositions of Examples 1 to 12, except that dutasteride was used as the active ingredient, and the specific ingredients and contents used are listed in Table 4 below.

[0078] [Table 4]

[0079]

[0080]

[0081] Experimental Example 1: Measurement of Tadalafil content

[0082] To confirm whether the injectable composition of the present disclosure contains a pharmacologically active ingredient at a known therapeutic level, a content of tadalafil used as a pharmacologically active ingredient was measured by high performance liquid chromatography (HPLC).

[0083] Specifically, an equivalent dose (mg) of each injectable composition containing 40 mg of tadalafil prepared in Examples 1 to 5, 8, 9 and 13 to 20 was precisely weighed and placed in a 100 mL volumetric flask, 50 mL of acetonitrile was added, and the flask was filled to the mark with 0.1% trifluoroacetic acid. The prepared solution was centrifuged at 3,500 rpm for 15 minutes, and then 5 mL of the supernatant was accurately transferred to a 20 mL volumetric flask, adjusted the volume to the mark with a diluent (a mixture of acetonitrile and 0.1% trifluoroacetic acid, 1 : 1), and filtered to prepare a test solution. The standard solution was prepared by placing 10.0 mg of accurately weighed tadalafil standard in a 100 mL volumetric flask, adding 50 mL of acetonitrile to completely dissolve it, and adjusting the volume to the mark with 0.1% trifluoroacetic acid, followed by filtering. The test solution and standard solution prepared by the above method were analyzed under the conditions of an ultraviolet spectrophotometer measuring wavelength of 285 nm, a ZORBAX Rx-C8 (4.6 x 250 mm, 5 μm, 80 Å) or equivalent column, a flow rate of 1.5 mL / min, and an injection volume of 20 μL, and each content of tadalafil contained in the compositions according to Examples was quantified as the average value of three analyses. The results are shown in Table 5 and 6.

[0084] [Table 5]

[0085]

[0086] [Table 6]

[0087]

[0088]

[0089] As a result, the pharmaceutical compositions of Examples 1 to 5, 8, 9, and 13 to 20 were all confirmed to be within ± 10% of the standard content of tadalafil (100%).

[0090]

[0091] Experimental Example 2. Confirmation of pharmacokinetics (in vivo)

[0092] Experimental Example 2-1. PK profile analysis of injectable composition of the present disclosure

[0093] An in vivo pharmacokinetic (PK) test was performed to verify the drug release behavior of the injectable composition of the present disclosure.

[0094] Specifically, each composition according to Examples was filled into a disposable syringe, and a 4.65 mg equivalent dose of tadalafil was injected into the thigh muscles of four 8-week-old SD rats (male) weighing an average of 300 g. The concentration of tadalafil in plasma samples of SD rats was analyzed by liquid chromatography-mass spectrometry (LC-MS / MS) to determine the pharmacokinetic (PK) profile.

[0095] As a result, as shown in FIG. 1, the compositions of Examples 1, 2, 3, and 8 were confirmed to be formulations capable of maintaining the blood concentration of tadalafil at a constant concentration or higher for one month or more, thus indicating that the injectable composition of the present disclosure is usefully employed as a sustained-release injectable preparation capable of improving the convenience of patient medication and continuously maintaining the efficacy.

[0096] In addition, as shown in FIG. 2, the compositions of Examples 11 and 12 exhibited a slightly higher second burst compared to the composition of Example 3, whereas they exhibited an equivalent level of the first burst. This indicated that the composition of the present disclosure, even when containing dimethylacetamide as a co-solvent, maintained the blood concentration of tadalafil at a constant concentration for one month or more and exhibited better sustained release.

[0097]

[0098] Experimental Example 2-2. Analysis of PK profiles of injectable compositions depending on lipid type

[0099] In order to confirm the drug release behavior of injectable compositions depending on lipid type, the PK profiles of the composition of Comparative Example 1 containing tocopherol and the composition of Example 3 containing castor oil were confirmed. The specific experimental method is the same as Experimental Example 2-1, and the results are shown in Table 7 and FIG. 3.

[0100] [Table 7]

[0101]

[0102] As a result, it was confirmed that the composition of Example 3 did not have a higher first burst or second burst of tadalafil than the composition of Comparative Example 1, and that the blood concentration of tadalafil was maintained at a constant concentration for one month or more. This indicated that the composition of the present disclosure containing castor oil as a lipid is more stable and exhibits better sustained release while reducing drug side effects.

[0103] Experimental Example 3. Confirmation of dissolution rate of injectable compositions depending on type of active ingredient (in vitro)

[0104] To confirm that the injectable compositions of the present disclosure exhibit good dissolution rates even when containing other active ingredients, the dissolution rates were checked for the compositions of Comparative Examples 3 and 4 containing dutasteride as the active ingredient.

[0105] The dissolution test for Comparative Examples 3 and 4 was conducted according to the dissolution test method 1 described in the Korean Pharmacopoeia, and the specific dissolution conditions are as follows.

[0106] <Dissolution conditions>

[0107] - Dissolution method: Korean Pharmacopoeia, Method 1 (Rotating basket method)

[0108] - Dissolution solution: 900 mL of solution containing 0.5% w / v sodium dodecyl sulfate

[0109] - Dissolution temperature: 37 ± 0.5℃

[0110] - Rotation speed: 25 rpm

[0111] - Test time: 1 hour, 3 hours, 6 hours, 12 hours, and 24 hours

[0112] As a result, as shown in FIG. 4, the composition of Comparative Example 3 containing dutasteride as the active ingredient and tocopherol as the lipid had a 24-hour dissolution rate of 46% or more, whereas the composition of Comparative Example 4 containing dutasteride as the active ingredient and castor oil as the lipid had a 24-hour dissolution rate of 15% or less. These results confirmed that even compositions containing castor oil as the lipid are not suitable for sustained release formulations because of the significantly lower dissolution rate when the active ingredient is dutasteride.

[0113] Experimental Example 4: Confirmation of local tolerance (in vivo)

[0114] In order to confirm the safety of the injectable composition of the present disclosure, an in vivo local tolerance test was conducted.

[0115] Specifically, each composition according to Examples was filled into a disposable syringe, and a 4.65 mg equivalent dose of tadalafil was injected into the thigh muscles of 8-week-old SD rats (male) weighing an average of 300 g. After 3, 7, 14, 30, and 45 days, an autopsy was performed to visually confirm the presence or absence of edema, redness (erythema), induration, necrosis, and exudate at the injection site.

[0116] As a result, as shown in FIG. 5, the compositions of Examples 1 and 3 did not induce any irritation at the injection site, such as edema, redness, induration, etc., at any time point during autopsy, indicating that the injectable composition of the present disclosure is safe in vivo for a long period of time.

[0117] Experimental Example 5. Confirmation of stability (in vitro)

[0118] Experimental Example 5-1. Formulation stability test of injectable composition of the present disclosure

[0119] In order to confirm the formulation stability of the injectable composition of the present disclosure, an in vitro stability test was conducted.

[0120] Specifically, each composition according to Examples was filled into a vial, stored under the conditions of 25℃ ± 2℃, 40℃ ± 2℃ (75% ± 5% RH), and the content was evaluated at 1 month, 3 months, and 6 months after storage using the same method as Experimental Example 1. The results are shown in Table 8.

[0121] [Table 8]

[0122]

[0123] As a result, the compositions of Examples 1, 3, and 5 maintained almost no change in the content of tadalafil for up to 6 months under each condition, thereby confirming the excellent content stability of the composition of the present disclosure.

[0124] Experimental Example 5-2. Formulation stability test of injectable compositions depending on lipid type

[0125] In order to confirm the formulation stability of injectable compositions depending on lipid type, the composition of Example 10 and the composition of Comparative Example 2 were stored under accelerated conditions (40℃ ± 2℃, 75% ± 5% RH) and harsh conditions (60℃), and the content was evaluated at 1 week, 2 weeks, and 4 weeks using the same method as Experimental Example 1. The results are shown in Table 9.

[0126] [Table 9]

[0127]

[0128] As a result, it was confirmed that the composition of Comparative Example 2 significantly decreased the content of tadalafil to 70% or less in Week 4 under harsh conditions, and the composition of Example 10 maintained almost no change in the content of tadalafil for up to 4 weeks under both accelerated and harsh conditions. This confirmed that the composition of the present disclosure has excellent content stability.

[0129] As described above, the present disclosure has been described in detail through preferred Examples, but the scope of the present disclosure is not limited to the specific Examples of the present disclosure and should be interpreted by the claims. Further, those skilled in the art should understand that many modifications and variations can be made without departing from the scope of the present disclosure.

Claims

1.An injectable composition comprising tadalafil or a pharmaceutically acceptable salt thereof, a lipid, and a co-solvent.2.The injectable composition of claim 1, wherein the lipid is any one selected from the group consisting of castor oil, safflower oil, sesame oil, olive oil, peanut oil, almond oil, camellia oil, corn oil, cottonseed oil, soybean oil, medium-chain triglycerides, pharmaceutically acceptable salts thereof, and mixtures thereof.3.The injectable composition of claim 1, wherein the lipid is castor oil, a pharmaceutically acceptable salt thereof, or a mixture thereof.4.The injectable composition of claim 1, wherein the co-solvent is any one selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, benzyl alcohol, dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, and mixtures thereof.5.The injectable composition of claim 1, wherein the co-solvent is N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl benzoate, dimethylacetamide, ethanol or a mixture thereof.6.The injectable composition of claim 1, wherein the tadalafil or the pharmaceutically acceptable salt thereof is contained in an amount of 30 to 600 mg per volume (mL) of the injectable composition.7.The injectable composition of claim 1, wherein the tadalafil or the pharmaceutically acceptable salt thereof is contained in an amount of 1 to 50 wt% based on the total weight of the injectable composition.8.The injectable composition of claim 1, wherein the lipid is contained in an amount of 5 to 50 wt% based on the total weight of the injectable composition.9.The injectable composition of claim 1, wherein the co-solvent is contained in an amount of 40 to 90 wt% based on the total weight of the injectable composition.10.The injectable composition of claim 1, wherein the injectable composition is used as a therapeutic agent for benign prostatic hyperplasia or erectile dysfunction.11.The injectable composition of claim 1, wherein the injectable composition is a liquid preparation.12.The injectable composition of claim 1, wherein the injectable composition is for intramuscular injection, subcutaneous injection, or intradermal injection.13.The injectable composition of claim 1, wherein the injectable composition is administered once a month.

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