SUSTAINED-RELEASE FORMULATION COMPOSITION

Abstract

An oil gel pharmaceutical composition, contains a liquid oil, a pharmaceutically acceptable gelator, a pharmaceutically acceptable stabilizer, and a pharmaceutically active component. The pharmaceutical composition is particularly suitable for a pharmaceutical preparation having anesthetic and analgesic activity, has good release duration and stability, can be used for injection and topical administration, has good patient tolerance and very few side effects.

Claims

1. A pharmaceutical composition, comprising the following components: a. a liquid oil b. a pharmaceutically acceptable gelator, selected from one or more of fatty acid glycerides of formula I: ##STR00005## wherein R′ and R″ may be identical or different and are each independently selected from H or RaCO, and R′″ is selected from RaCO; each Ra is independently selected from saturated or unsaturated aliphatic hydrocarbyl; c. a pharmaceutically acceptable stabilizer, selected from one or more of compounds of formula II or formula III: the compound of formula II being ##STR00006## wherein Rs is selected from H, ##STR00007## R.sub.1 and R.sub.2 are identical or different and are each independently selected from saturated or unsaturated aliphatic hydrocarbyl; R.sub.3, R.sub.4 and R.sub.5 are identical or different and are each independently selected from H or alkyl; L is selected from alkylene; the compound of formula III being ##STR00008## wherein R is selected from alkyl; and d. at least one pharmaceutically active ingredient.

2. The pharmaceutical composition according to claim 1, wherein in the formula I, each Ra is independently selected from alkyl; preferably, each Ra is independently selected from C.sub.1-40 alkyl; more preferably, each Ra is independently selected from C.sub.7-40 alkyl; preferably, R′ and R″ are selected from H, and R′″ is selected from (C.sub.11-40 alkyl)C(═O); or, R′ is selected from H, R″ is selected from RaCO, and a total number of carbon atoms in the Ra alkyl selected for each of R″ and R′″ independently is greater than 18; or, R′, R″ and R′″ are all selected from RaCO, and a total number of carbon atoms in the Ra alkyl selected for each of R′, R″ and R′″ independently is greater than 17; preferably, in the formula II, R.sub.1 and R.sub.2 are identical or different and are each independently selected from C.sub.10-30 saturated or unsaturated aliphatic hydrocarbyl, e.g., C.sub.13-21 alkyl; R.sub.3, R.sub.4 and Rs are identical or different and are each independently selected from H or C.sub.1-10 alkyl, for example, from H, methyl or ethyl; L is selected from C.sub.1-10 alkylene; preferably, L is selected from C.sub.1-6 aklylene, and for example, is methylene or ethylidene; in the compound of formula III, R is selected from C.sub.1-10 alkyl, e.g., C.sub.8-10 alkyl.

3. The pharmaceutical composition according to claim 1, wherein the component b pharmaceutically acceptable gelator includes, for example, one or more of glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl monopalmitate stearate, glyceryl dipalmitate stearate, glyceryl monopalmitate, glyceryl dipalmitate and glyceryl palmitate stearate; the component c pharmaceutically acceptable stabilizer is selected from one or more of HSPC (hydrogenated soybean phosphatidylcholine), DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DSPC (distearoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soybean phospholipid), EPC (egg yolk phospholipid), rapeseed phospholipid, sunflower phospholipid, DEPC (dierucoylphosphatidylcholine), DOPC (dioleoylphosphatidylcholine), POPC (palmitoyloleoylphosphatidylcholine), sphingomyelin, distearoyl phosphatidic acid (DSPA), dioleoylphosphatidylethanolamine (DOPE), dipalmitoyl phosphatidic acid (DPPA), myristoyl lysophosphatidylcholine (M-lysoPC), palmitoyl lysophosphatidylcholine (P-lysoPC), 1-stearoyl lysophosphatidylcholine (S-lysoPC), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylserine (DPPS), phosphatidylinositol (PI) and cholesterol (CHO).

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises e. at least one pharmaceutically acceptable solvent; and/or the pharmaceutical composition may further comprise g. a pharmaceutically acceptable release modifier; and/or the pharmaceutical composition may further comprise f a pharmaceutically acceptable acid.

5. The pharmaceutical composition according to claim 1, wherein the liquid oil is selected from one or a combination of more of castor oil, sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, tea oil, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, palm oil, palm kernel oil, sunflower oil, medium-chain triglyceride, glyceryl dioleate and glyceryl monooleate; the at least one pharmaceutically active ingredient is not limited to a therapeutic type, and may be an anti-inflammatory drug, a local anesthetic, an analgesic, an anti-psychiatric drug, an anxiolytic, a sedative-hypnotic drug, an antidepressant, an antihypertensive drug, a steroid hormone, an antiepileptic drug, an antiseptic, an anticonvulsant, an anti-Parkinson drug, a central nervous stimulant, an antipsychotic, an antiarrhythmic, an antianginal, an antithyroid drug, an antidote, an antiemetic, a hypoglycemic drug, an anti-tubercular drug, an anti-HIV drug, an anti-HBV drug, an antineoplastic, an anti-rejection drug or a mixture thereof.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable release modifier is selected from small-molecule esters and surfactants; the small-molecule esters are glyceryl triacetate, isopropyl stearate, isopropyl laurate, isopropyl palmitate, isopropyl myristate and benzyl benzoate; the pharmaceutically acceptable acid is selected from acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, linoleic acid, sorbic acid, caprylic acid, pelargonic acid, lauric acid, palmitic acid, oleic acid, hydrochloric acid, phthalic acid, capric acid, myristic acid, propionic acid, butyric acid, heptanoic acid, valeric acid, malic acid, tartaric acid, oxalic acid, citric acid, ascorbic acid, salicylic acid, caffeic acid and vitamin E succinic acid.

7. The pharmaceutical composition according to claim 1, wherein the liquid oil accounts for about 20% to about 90% (w/w) of a total amount of the composition; the gelator accounts for 2% to 50% (w/w) of the total amount of the composition; the stabilizer accounts for 1% to 40% (w/w) of the total amount of the composition; the pharmaceutically active ingredient accounts for 0.01% to 50.0% (w/w) of the total amount of the composition; the total amount of the solvent accounts for 0% to 50% (w/w) of the total amount of the composition.

8. A preparation method for the pharmaceutical composition according to claim 1, comprising the following steps: (a1) mixing a liquid oil, a pharmaceutically acceptable gelator, a pharmaceutical stabilizer and a solvent, and stirring under a heating condition to obtain a clear and uniform mixed solution; (a2) adding at least one pharmaceutically active ingredient to the mixed solution, and stirring to form a uniform mixture; and (a3) cooling the uniform mixture formed in (a2) to room temperature. According to an embodiment of the present disclosure, the mixing in step (a1) further comprises adding at least one release modifier; for example, step (a1) may be mixing a liquid oil, a gelator, a pharmaceutical stabilizer and a pharmaceutically acceptable solvent with a release modifier.

9. A sustained-release formulation comprising the pharmaceutical composition according to claim 1, wherein the formulation is administered as a depot formulation; preferably, the formulation is injectable or the formulation can be administered topically.

10. The formulation according to claim 9, further comprising packaging filled with the formulation, the packaging being selected from one or more of a vial, a pre-filled syringe and a cartridge.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0102] FIGS. 1A and 1B show rheological results of composition 1010 at 2-8° C. and 25° C.

[0103] FIGS. 1C and 1D show rheological results of composition 1013 at 2-8° C. and 25° C.

[0104] FIGS. 1E to 1G show rheological results of compositions 1051, 1052, 1030 and 1031.

[0105] FIG. 1H shows graphs of viscosity-temperature changes for compositions 1010 and 1013.

[0106] FIG. 1I shows graphs of viscosity-temperature changes for compositions 1051 and 1052.

[0107] FIG. 1J shows graphs of viscosity-rotational speed changes for compositions 1053 and 1054.

[0108] FIGS. 2A and 2B show bupivacaine and meloxicam plasma concentration-time curves for composition 1047.

[0109] FIGS. 2C and 2D show bupivacaine and meloxicam plasma concentration-time curves for composition 1048.

[0110] FIG. 3 shows the effects of compositions 1076, 1077 and 1078 on the mechanical hyperalgesia of a rat CFA inflammatory pain model. Pre indicates the basal mechanical pain threshold before molding, and the black solid dots indicate statistical differences (p<0.05) in the results relative to the model group.

[0111] FIGS. 4A and 4B show ropivacaine and meloxicam plasma concentration-time curves for composition 1079.

[0112] FIGS. 5A and 5B show ropivacaine and meloxicam plasma concentration-time curves for composition 1080.

[0113] FIGS. 5C and 5D show ropivacaine and meloxicam plasma concentration-time curves for composition 1081.

DETAILED DESCRIPTION

[0114] The technical scheme of the present disclosure will be further illustrated in detail with reference to the following specific examples. It should be understood that the following examples are merely exemplary illustration and explanation of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All techniques implemented based on the content of the present disclosure described above are encompassed within the protection scope of the present disclosure.

[0115] Unless otherwise stated, the starting materials and reagents used in the following examples are all commercially available products or can be prepared using known methods.

[0116] Materials: [0117] Castor oil: CO; [0118] Glyceryl monostearate: IMWITOR® 900K; Cithrol GMS 40, Geleol; [0119] Mixed fatty acid glycerides (stearin): stearin 36, stearin 38, SUPPOCIRE AM, SUPPOCIRE CM, GELUCIRE 43/01, SOFTISAN 378; [0120] Glyceryl distearate: Precirol ATOS; [0121] Glyceryl behenate: COMPRITOL 888 ATO; [0122] Phospholipid: SPC, HSPC, DMPC, DPPC, DSPC, DEPC, EPC, and DOPC.

Example 1

Effects of Stabilizers on Appearance of Compositions

[0123] Compositions comprising different gelators were prepared according to Tables 1-1 to 1-3, and let stand at room temperature for a long period of 20 months, and the compositions were compared with standard colorimetric solutions Y (yellow) 1-10 to examine the compositions for changes in apparent color.

TABLE-US-00001 TABLE 1-1 Apparent colors of compositions comprising glyceryl monostearate as gelator after standing for a long period of time Corresponding IMWITOR color level CO 900K ROP MLX NMP SPC HSPC BA Month No. wt % wt % wt % wt % wt % wt % wt % wt% 0 h 20 1001 68.8 15 2.5 0.19 3.51 0 0 10 Y6~7 Y8~9 1002 75.3 8.5 2.5 0.19 3.51 0 0 10 Y6~7 Y > 10 1003 59.1 22.2 5 0.19 3.51 0 0 10 Y6~7 Y8~9 1004 51.6 22.2 2.5 0.19 3.51 10 0 10 Y6~7 Y7~8 1005 58.8 22.2 2.5 0.19 3.51 0 10 10 Y6~7 Y7~8

TABLE-US-00002 TABLE 1-2 Apparent colors of compositions comprising stearin as gelator after standing for along period of time Corresponding color level CO Stearin 36 Stearin 38 ROP MLX NMP BA Month No. wt % wt % wt % wt % wt % wt % wt % 0 h 20 1006 53.8 30 0 2.5 0.19 3.51 10 Y6~7 Y > 10 1007 53.8 0 30 2.5 0.19 3.51 10 Y6~7 Y9-10

TABLE-US-00003 TABLE 1-3 Apparent color of composition comprising glyceryl behenate as gelator after standing for a long period of time COMPRITOL Corresponding CO 888 ROP BA color level wt ATO wt MLX NMP wt Month No. % wt % % wt % wt % % 0 h 20 1008 61.6 22.2 2.5 0.19 3.51 10 Y6~7 Y9-10

[0124] The present disclosure unexpectedly revealed that all the oleogel formulations comprising only a fatty acid glyceride as the gelator became darkened to varying degrees during long-term retention. After the compositions with added stabilizers (e.g., SPC and HSPC) were let stand for a long period of 20 months, their apparent color levels were between Y7 and Y8. Their color changes were significantly smaller than those of other oleogel compositions, indicating that the addition of stabilizers could significantly increase the stability of oleogel compositions in appearance.

Example 2

Study on Oil-Holding Capacity of Compositions

[0125] Pharmaceutical compositions comprising different proportions of the gelator were prepared according to each of the components shown in Tables 2-1 to 2-9 below. After 0.5 g of a pharmaceutical composition was weighed into a centrifuge tube and centrifuged at different rotational speeds, the centrifuge tube was inverted, and oil separation in the composition was observed.

TABLE-US-00004 TABLE 2-1 Oil-holding capacity study of oleogel compositions comprising no stabilizer CO SUPPOCIRE SUPPOCIRE BUP GELUCIRE SOFTISAN wt AM CM wt 43/01 378 14000 rpm No. % wt % wt % % wt % wt % 10 min 1028 82 10 0 8 0 0 Not centrifuged, turbid solution 1029 72 20 0 8 0 0 Oil separated 1030 82 0 10 8 0 0 Oil separated 1031 72 0 20 8 0 0 Oil separated 1032 82 0 0 8 10 0 Oil separated 1034 72 0 0 8 0 20 Oil separated 1035 52 0 0 8 0 40 Oil separated

TABLE-US-00005 TABLE 2-2 Comparison of the oil-holding capacities of oleogel compositions with added stabilizers 9000 rpm 15 min CO NMP BUP MLX ATO5 SPC Standing Standing No. wt % wt % wt % wt % wt % wt % at 40° C. at 25° C. 1009 68.82 10 6 0.18 15 / Oil Oil separated separated 1012 58.82 10 6 0.18 15 10 No oil No oil separated separated

TABLE-US-00006 TABLE 2-3 Oil-holding capacity study of oleogel compositions with respect to the amount of stabilizers CO NMP BUP MLX ATO5 SPC 9000 rpm 15 min No. wt % wt % wt % wt % wt % wt % 40° C. 25° C. 1014 68.85 10 5 0.15 15 1 No oil Oil separated separated 1015 66.85 10 5 0.15 15 3 No oil Oil separated separated 1016 64.85 10 5 0.15 15 5 No oil No oil separated separated 1017 61.85 10 5 0.15 15 8 No oil No oil separated separated

TABLE-US-00007 TABLE 2-4 Oil-holding capacity study of oleogel compositions with respect to the amount of stabilizers CO DMSO BUP MLX ATO5 SPC 9000 rpm15 min No. wt % wt % wt % wt % wt % wt % 40° C. 25° C. 1044 67.82 5 6 0.18 20 1 No oil No oil separated separated 1045 66.82 5 6 0.18 20 2 No oil No oil separated separated 1046 65.82 5 6 0.18 20 3 No oil No oil separated separated

TABLE-US-00008 TABLE 2-5 Oil-holding capacity study of oleogel compositions with respect to the amount of stabilizers CO DMSO BUP MLX Geleol DOPC 9000 rpm 15 min No. wt % wt % wt % wt % wt % wt % 40° C. 25° C. 1066 67.82 5 6 0.18 20 1 No oil separated No oil separated 1067 66.82 5 6 0.18 20 2 No oil separated No oil separated 1068 65.82 5 6 0.18 20 3 No oil separated No oil separated

TABLE-US-00009 TABLE 2-6 Oil-holding capacity study of oleogel compositions comprising stabilizers BUP 14000 CO BA wt MLX NMP ATO5 DPPC DMPC DSPC HSPC rpm No. wt % wt % % wt % wt % wt % wt % wt % wt % wt % 10 min 1024 61.76 7.84 8 0.24 2.16 15 5 0 0 0 No oil separated 1025 61.76 7.84 8 0.24 2.16 15 0 5 0 0 No oil separated 1026 61.76 7.84 8 0.24 2.16 15 0 0 5 0 No oil separated 1027 61.76 7.84 8 0.24 2.16 15 0 0 0 5 No oil separated

TABLE-US-00010 TABLE 2-7 Oil-holding capacity study of oleogel compositions comprising stabilizers CO BA DMSO BUP MLX ATO5 POPC DEPC EPC DOPC CHO 9000 rpm No. wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % 15 min 1039 61.76 5.44 4.56 8 0.24 15 5 0 0 0 0 No oil separated 1040 61.76 5.44 4.56 8 0.24 15 0 5 0 0 0 No oil separated 1041 61.76 5.44 4.56 8 0.24 15 0 0 5 0 0 No oil separated 1042 61.76 5.44 4.56 8 0.24 15 0 0 0 5 0 No oil separated 1043 61.76 5.44 4.56 8 0.24 15 0 0 0 0 5 Marginal oil separated at the edge

TABLE-US-00011 TABLE 2-8 Oil-holding capacity study of oleogel compositions comprising stabilizers CO BA GELUCIRE 9000 wt wt DMSO BUP MLX 43/01 POPC DEPC EPC DOPC rpm No. % % wt % wt % wt % wt % wt % wt % wt wt % 15 min 1069 59.7 4.3 5.7 10 0.3 15 5 0 0 0 No oil separated 1070 59.7 4.3 5.7 10 0.3 15 0 5 0 0 No oil separated 1071 59.7 4.3 5.7 10 0.3 15 0 0 5 0 No oil separated 1072 59.7 4.3 5.7 10 0.3 15 0 0 0 5 No oil separated

TABLE-US-00012 TABLE 2-9 Oil-holding capacity study of oleogel compositions comprising stabilizers Cithrol CO BA BUP GMS 40 SPC 9000 rpm No. wt % wt % wt % wt % wt % 15 min 1073 27 10 3 30 30 No oil separated 1075 72 0 3 20 5 No oil separated

[0126] Oil-holding capacity is one of the indicators for evaluating the structural stability of an oleogel. In order to ensure the ability of a gelator to solidify a liquid oil to prevent the liquid oil from separating during long-term standing, the oil-holding capacity of the formulation needs to be studied to determine the maximum oil-bearing capacity of the oleogel. The present disclosure unexpectedly revealed that the compositions comprising stabilizers had significantly improved oil-holding capacities and improved physical stability, and thus the risk of oil separation during storage was effectively reduced.

Example 3

Viscosity Measurements of Oleogel Compositions

[0127] Pharmaceutical compositions comprising different amounts of the stabilizer and organic solvent were prepared according to Tables 3-1 to 3-3. The starting auxiliary materials were mixed at 70° C., heated with stirring until a transparent and uniform solution was formed, and cooled to room temperature to form a solid gel-like substance. Subsequently, the viscosities of the pharmaceutical compositions were measured through the spindle method using a viscometer equipped with a No. 14 spindle at a temperature of 30° C. at a rotational speed of 10 rpm, and the viscosity measurements are shown in Tables 3-1 to 3-3 below.

TABLE-US-00013 TABLE 3-1 Viscosity measurements of pharmaceutical compositions comprising no stabilizer CO BA BUP ATO5 Viscosity No. wt % wt % wt % wt % cP 1058 79 0 6 15 98000 1059 69 10 6 15 93375

TABLE-US-00014 TABLE 3-2 Viscosity measurements of pharmaceutical compositions comprising different stabilizers CO BA BUP SPC wt wt DMSO NMP wt MLX ATO5 DEPC DOPC CHO wt Viscosity No. % % wt % wt % % wt % wt % wt % wt % wt % % cP 1040 61.76 5.44 4.56 0 8 0.24 15 5 0 0 0 5337.5 1042 61.76 5.44 4.56 0 8 0.24 15 0 5 0 0 6262.5 1043 61.76 5.44 4.56 0 8 0.24 15 0 0 5 0 5650 1011 63.82 0 0 10 6 0.18 10 0 0 0 10 5087.5

TABLE-US-00015 TABLE 3-3 Viscosity measurements of pharmaceutical compositions comprising different amounts of the organic solvent BA BUP SPC VE CO DMSO wt wt MLX ATO5 wt wt Viscosity No. wt % wt % % % wt % wt % % % cP 1056 56.61 5 10 8 0.24 15 5 0.15 2737.5 1057 51.61 5 15 8 0.24 15 5 0.15 3650

[0128] The present disclosure unexpectedly revealed that the viscosity of the pharmaceutical composition could be significantly reduced by adding a stabilizer (e.g., SPC, DEPC, CHO, DOPC, etc.), and meanwhile, the amount of the organic solvent also affected the viscosity of the entire system. Therefore, the viscosity of the pharmaceutical composition can be optimized by adjusting the proportions of the stabilizer and the organic solvent, so that the pharmaceutical composition is convenient for clinical administration.

Example 4

Syringeability Study

[0129] Oleogel compositions comprising different organic solvents and different stabilizers were formulated according to Tables 4-1 to 4-4, and the compositions in the tables were subjected to syringeability tests to determine the maximum pushing forces. The test results are shown in Tables 4-1 to 4-4 below.

TABLE-US-00016 TABLE 4-1 Syringeability study Maximum pushing CO BA BUP ATO5 force No. wt % wt % wt % wt % kg 1058 79 0 6 15 0.92 1059 69 10 6 15 0.57

TABLE-US-00017 TABLE 4-2 Syringeability study with respect to different amounts of the organic solvent CO DMSO BA BUP MLX ATO5 SPC VE Maximum pushing No. wt % wt % wt % wt % wt % wt % wt % wt % force kg 1056 56.61 5 10 8 0.24 15 5 0.15 0.5 1057 51.61 5 15 8 0.24 15 5 0.15 0.41 1055 61.61 4.56 5.44 8 0.24 15 5 0.15 0.78 1064 37.2 15 15 6 1.8 20 5 0 0.89

TABLE-US-00018 TABLE 4-3 Syringeability study with respect to different stabilizers Maximum pushing CO BA DMSO BUP MLX ATO5 DEPC DOPC CHO force No. wt % wt % wt % wt % wt % wt % wt % wt % wt % kg 1040 61.76 5.44 4.56 8 0.24 15 5 0 0 0.67 1042 61.76 5.44 4.56 8 0.24 15 0 5 0 0.56 1043 61.76 5.44 4.56 8 0.24 15 0 0 5 0.47

TABLE-US-00019 TABLE 4-4 Syringeability results of pharmaceutical compositions comprising different amounts of the stabilizer Cithrol Maximum CO BA BUP DMSO MLX GMS 40 SPC VE pushing force No. wt % wt % wt % wt % wt % wt % wt % wt % kg 1050 61.61 5.44 8 4.56 0.24 15 5 0.15 0.55 1051 51.61 5.44 8 4.56 0.24 20 10 0.15 0.62

[0130] Generally, for the ease of administration by doctors, the syringeability in clinical administration requires the maximum pushing force not to be greater than 2 kg.

[0131] In the present disclosure, the effect of the amount of the organic solvent on syringeability was studied. The results show that the pushing force can be reduced by increasing the amount of the organic solvent, which is beneficial to clinical administration. In addition, the pushing force can also be reduced by adding other stabilizers to the oleogel composition.

Example 5

Rheological Study of Compositions

[0132] Oleogel compositions were prepared according to Tables 5-1 to 5-4 and subjected to rheological studies. Rheometer model: TA DHR-1 Sample amount: 1 mL. Measurement mode: oscillation mode: time scanning, fixed strain 0.5%, frequency 1 Hz; oscillation mode: frequency scanning, fixed strain 0.5%, frequency scanning range: 0.1-100 rad/s; flow mode: viscosity scanning, shear rate range: 0.01-100 1/s; flow mode: viscosity scanning at varying temperatures, temperature varying range: 20-60° C., fixed shear rate: 0.1 1/s.

TABLE-US-00020 TABLE 5-1 Components of compositions CO NMP BUP MLX ATO5 SPC No. wt % wt % wt % wt % wt % wt % 1010 63.82 10 6 0.18 20 / 1013 53.82 10 6 0.18 20 10

TABLE-US-00021 TABLE 5-2 Components of compositions Cithrol CO BA BUP DMSO MLX GMS 40 SPC VE No. wt % wt % wt % wt % wt % wt % wt % wt % 1051 51.61 5.44 8 4.56 0.24 20 10 0.15 1052 56.61 5.44 8 4.56 0.24 20  5 0.15

TABLE-US-00022 TABLE 5-3 Components of compositions SUPPOCIRE CO CM BUP No. wt % wt % wt % 1030 82 10 8 1031 72 20 8

TABLE-US-00023 TABLE 5-4 Components of compositions CO BA BUP DMSO MLX ATO5 SPC VE No. wt % wt % wt % wt % wt % wt % wt % wt % 1053 51.61 5.44 8 4.56 0.24 20 10 0.15 1054 56.61 5.44 8 4.56 0.24 20  5 0.15

[0133] The parameters storage modulus G′ and loss modulus G″ in rheology can be used to evaluate gel properties. Theoretically, the larger the storage modulus G′ of a glyceride, the greater the gel strength and the more stable the gel network structure. When the storage modulus (G′) is greater than the loss modulus (G″), the sample exhibits gel properties. FIGS. 1A to 1G show the rheological properties of the oleogel compositions in Tables 5-1 to 5-3. The present disclosure unexpectedly revealed that the SPC-comprising composition (1013) in which G′ was greater than G″ exhibited significant gel properties, while compositions comprising no SPC (1010, 1030 and 1031) did not exhibit gel properties. Meanwhile, the gel strength of the formulation could be improved by increasing the amount of the stabilizer (1051 and 1052).

[0134] FIGS. 1H and 1I show the temperature-dependent trends of the viscosities of compositions 1010, 1013, 1051 and 1052, from which the gelation temperatures of the compositions can be inferred, and the results are shown in Table 5-5. It can be seen from Table 5-5 that the gelation temperature of the composition can be lowered by adding SPC, which is more beneficial to scale-up production and filling.

TABLE-US-00024 TABLE 5-5 Gelation temperatures of compositions Gelation No. temperature (° C.) 1010 49.1 1013 45.2 1051 40.2 1052 40.2

[0135] FIG. 1J shows the rotational speed-dependent trends of the viscosities of compositions 1053 and 1054, from which it can be seen that the oleogel compositions of the present disclosure exhibit shear thinning properties, which is beneficial to clinical administration. Meanwhile, the increase in the amount of the stabilizer SPC led to a certain decrease in the viscosity of the composition.

Example 6

Solidification Temperature Study

[0136] Oleogel compositions were prepared according to Tables 6-1 to 6-3 and observed under a microscope for the solidification temperatures in cooling the dissolved compositions, and the effects of organic solvents and stabilizers on the solidification temperature were studied. The results are shown in Tables 6-1 to 6-3 below.

TABLE-US-00025 TABLE 6-1 Solidification temperatures of compositions comprising no stabilizer Solidification CO BA BUP ATO5 temperature No. wt % wt % wt % wt % ° C. 1058 79 0 6 15 52 1059 69 10 6 15 45

TABLE-US-00026 TABLE 6-2 Solidification temperatures of compositions comprising different organic solvents Solidification CO DMSO BA BUP MLX ATO5 SPC VE temperature No. wt % wt % wt % wt % wt % wt % wt % wt % ° C. 1056 56.61 5 10 8 0.24 15 5 0.15 41 1057 51.61 5 15 8 0.24 15 5 0.15 40 1049 61.61 10 0 8 0.24 15 5 0.15 44 1055 61.61 4.56 5.44 8 0.24 15 5 0.15 42

TABLE-US-00027 TABLE 6-3 Solidification temperatures of compositions comprising different stabilizers Solidification CO BA DMSO BUP MLX ATO5 POPC DEPC EPC DOPC CHO temperature No. wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % ° C. 1039 61.76 5.44 4.56 8 0.24 15 5 0 0 0 0 43 1040 61.76 5.44 4.56 8 0.24 15 0 5 0 0 0 38 1041 61.76 5.44 4.56 8 0.24 15 0 0 5 0 0 38 1042 61.76 5.44 4.56 8 0.24 15 0 0 0 5 0 40 1043 61.76 5.44 4.56 8 0.24 15 0 0 0 0 5 44

[0137] The present disclosure unexpectedly revealed that the solidification temperature of the composition could be lowered by adding an organic solvent and a stabilizer, which was beneficial to production and filling.

Example 7

[0138] Oleogel Compositions Comprising Different Active Ingredients Oleogel compositions comprising different main active ingredients were prepared according to each of the components shown in Table 7-1 below. The starting auxiliary materials were mixed at 70° C., heated with stirring until a transparent and uniform solution was formed, and cooled to room temperature to form a solid gel-like substance.

TABLE-US-00028 TABLE 7-1 Compositions comprising different active ingredients CO BA ROP DMSO MLX Geleol ATO5 SPC VE No. wt % wt % wt % wt % wt % wt % wt % wt % wt % 1036 66.76 5 3 5 0.09 15 0 5 0.15 1037 61.76 5 3 5 0.09 20 0 5 0.15 1038 66.76 5 3 5 0.09 0 15 5 0.15

TABLE-US-00029 TABLE 7-2 Compositions comprising different active ingredients CO DMSO BA LBUP TAC KTL PRX ATO5 SPC No. wt % wt % wt % wt % wt % wt % wt % wt % wt % 1060 66.91 5 5 3 0 0 0.09 15 5 1061 67 5 5 0 3 0 0 15 5 1062 65 5 5 0 0 5 0 15 5

Example 8

Pharmaceutical Compositions Comprising Different Concentrations of Active Ingredient and Antioxidant

[0139] Oleogel compositions comprising different concentrations of the active ingredient and antioxidant were prepared according to each of the components shown in Table 8 below. The starting auxiliary materials were mixed at 70° C., heated with stirring until a transparent and uniform solution was formed, and cooled to room temperature to form a solid gel-like substance.

TABLE-US-00030 TABLE 8 Pharmaceutical compositions comprising different concentrations and antioxidants CO DMSO BUP MLX ATO5 SPC VE Thioglycerol BHA BHT No. wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % 1018 61.71 10 8 0.24 15 5 0 0.05 0 0 1022 61.71 10 8 0.24 15 5 0 0 0.05 0 1023 61.71 10 8 0.24 15 5 0 0 0 0.05 1082 66.61 10 8 0.24 10 5 0 0 0 0.15 1019 59.55 10 10 0.3 15 5 0.15 0 0 0 1020 63.67 10 6 0.18 15 5 0.15 0 0 0

Example 9. Pharmaceutical Compositions Comprising No Organic Solvent or Comprising Different Organic Solvents

[0140] Oleogel compositions comprising different organic solvents were prepared according to each of the components shown in Table 9 below. The starting auxiliary materials were mixed at 70° C., heated with stirring until a transparent and uniform solution was formed, and cooled to room temperature to form a solid gel-like substance.

TABLE-US-00031 TABLE 9 Pharmaceutical compositions comprising no organic solvent or comprising different organic solvents CO DMSO NMP EtOH BA BUP MLX ATO5 SPC Thioglycerol BHT No. wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % wt % 1083 66.46 10 0 0 0 8 0.24 10 5 0.15 0.15 1084 66.61 0 0 0 10 8 0.24 10 5 0.15 0 1085 61.46 0 0 10 0 8 0.24 15 5 0.15 0.15 1086 59.85 0 10 0 0 5 0.15 15 10 0 0 1087 71.46 0 0 0 0 8 0.24 15 5 0.15 0.15

Example 10

In Vivo Administration of Oleogel Compositions

[0141] In vivo pharmacokinetic studies were carried out in dogs as follows. Beagles weighing about 10 kg were fasted for over 12 h (removing the feeding box) before the experiment, given ad libitum access to water, and given food 4 h after administration. Administration was performed to each group by subcutaneous injection at 6 mg/kg. The samples are shown in Table 10. Blood samples of about 0.5 mL were collected from the animals in each group into EDTA-2K+ anticoagulated blood collection tubes at 0 h before the administration, and at 0.5 h, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, and 96 h after the administration. Plasma was collected after the whole blood was centrifuged at 8000 rpm for 5 min, and then the drug concentrations in plasma samples were determined by LC-MS/MS.

TABLE-US-00032 TABLE 10 Formulas of compositions CO SPC NMP DMSO BUP MLX ATO5 No. wt % wt % wt % wt % wt % wt % wt % 1047 64.85 5  0 10 5 0.15 15 1048 64.85 5 10  0 5 0.15 15

[0142] The BUP and MLX plasma concentration-time curves within 96 h after administration of the composition are shown in FIGS. 2A to 2D.

Example 11

In Vivo Administration of Oleogel Compositions

[0143] Pharmacodynamic studies were carried out in rats as follows. The PWT value was measured once a day over three days before the experiment, and once before modeling on the fourth day as a pre-modeling basal value. Subsequently, 100 μL of CFA was administered to each rat in the right hind paws. The PWT value was measured once again 24 h after inflammation modeling as a post-modeling basal value. Compositions were subcutaneously injected into the footpad. The samples are shown in Table 11. Administration was not performed to the model group. The mechanical paw withdrawal thresholds (PWTs) of the rats were determined as the pain thresholds by irritating the middle part of the footpad of a hind limb with Von Frey monofilaments at different time points after the administration. The time points were 30 min, 1 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h and 92 h after the administration.

TABLE-US-00033 TABLE 11 Samples CO NMP BUP MLX ATO5 SPC No. wt % wt % wt % wt % wt % wt % 1076 54.7 10 10 0.3 15 10 1077 55 10 10 0 15 10 1078 60.8 11.1 0 0.3 16.7 11.1

[0144] The results are shown in FIG. 3. Before the modeling, the mechanical paw withdrawal thresholds (PWTs) of the rats in each group were all kept at 21-24 g; 24 h after the modeling, the mechanical paw withdrawal thresholds (PWTs) decreased to 4-6 g, indicating that the mechanical allodynia of the rats was very significant after the CFA modeling. Composition 1076 significantly increased the PWT value (p<0.05) in rats only 30 min after administration and the effect persisted until hour 96. The difference is of statistical significance (p<0.05). Composition 1078 produced an analgesic effect 4 h after administration (p<0.05), and the analgesic effect persisted until hour 12 and then disappeared (p>0.05), indicating that the effect lasted for a period of time between 12 h and 24 h. Composition 1077 produced no analgesic effect until hour 8 (p<0.05), and the analgesic effect persisted until hour 12, then fluctuated, and appeared again at 48 h (p<0.05).

Example 12

In Vivo Administration of Oleogel Compositions

[0145] In vivo pharmacokinetic studies were carried out in dogs as follows. Beagles weighing about 10 kg were fasted for over 12 h (removing the feeding box) before the experiment, given ad libitum access to water, and given food 4 h after administration. Administration was performed to each group by subcutaneous injection at 6 mg/kg. The samples are shown in Table 12. Blood samples of about 0.5 mL were collected from the animals in each group into EDTA-2K+ anticoagulated blood collection tubes at 0 h before the administration, and at 0.5 h, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, and 96 h after the administration. Plasma was collected after the whole blood was centrifuged at 8000 rpm for 5 min, and then the drug concentrations in plasma samples were determined by LC-MS/MS.

TABLE-US-00034 TABLE 12 Formulas of compositions CO VES SPC ATO 5 BA ROP MLX NMP No. wt % wt % wt % wt % wt % wt % wt % wt % 1079 30.46 18.2 27.3 9.1 9.1 4.5 0.14 1.2

[0146] The ROP and MLX plasma concentration-time curves within 96 h after administration of the composition are shown in FIGS. 4A to 4B.

Example 13

In Vivo Administration of Oleogel Compositions

[0147] In vivo pharmacokinetic studies were carried out in dogs as follows. Beagles weighing about 10 kg were fasted for over 12 h (removing the feeding box) before the experiment, given ad libitum access to water, and given food 4 h after administration. Administration was performed to each group by subcutaneous injection at 6 mg/kg. The samples are shown in Table 13. Blood samples of about 0.5 mL were collected from the animals in each group into EDTA-2K+ anticoagulated blood collection tubes at 0 h before the administration, and at 0.5 h, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, and 96 h after the administration. Plasma was collected after the whole blood was centrifuged at 8000 rpm for 5 min, and then the drug concentrations in plasma samples were determined by LC-MS/MS.

TABLE-US-00035 TABLE 13 Formulas of compositions CO SPC BA DMSO MLX ATO5 Benzoic acid Maleic acid ROP No. wt % wt % wt % wt % wt % wt % wt % wt % wt % 1080 59.82 5 4 6 0.18 15 4 0 6 1081 59.82 5 4 6 0.18 15 0 4 6

[0148] The ROP and MLX plasma concentration-time curves within 96 h after administration of the composition are shown in FIGS. 5A to 5D.

[0149] The exemplary embodiments of the present disclosure have been described above. However, the scope of the present disclosure is not limited to the above embodiments. Any modification, equivalent, improvement and the like made without departing from the spirit and principle of the present disclosure shall fall within the protection scope of the present disclosure.