Pharmaceutical composition of diltiazem hydrochloride, preparation method therefor, and application thereof

Abstract

Disclosed herein is a pharmaceutical composition comprising diltiazem hydrochloride. The composition is preferably formulated as a gel and contains diltiazem hydrochloride together with excipients such as propylene glycol, tartaric acid, and a gel matrix. Also disclosed are a method for preparing the composition and a method for treating anal fissures and / or postoperative pain associated with anal fissures or hemorrhoids.

Description

[0001] 197656.00028

[0002] PHARMACEUTICAL COMPOSITION OF DILTIAZEM HYDROCHLORIDE, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Patent Application Serial No. 18 / 901,715 filed on September 30, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0005] TECHNICAL FIELD

[0006] The present invention relates particularly to a pharmaceutical composition of diltiazem hydrochloride, a preparation method therefor, and an application thereof, and belongs to the field of pharmaceutical preparations.

[0007] BACKGROUND ART

[0008] An anal fissure is a small ulcer resulting from the laceration of anal canal skin layer under the dentate line, and often causes severe perianal pain. It is very common in young and middle- aged people, with the typical clinical manifestations of pain, hematochezia, and constipation. The etiology of anal fissure remains unclear, and may be associated with a variety of factors. Most anal fissures are directly caused by mechanical trauma during a bowel movement due to long-term constipation and dried stool. In addition, diarrhea is also one of the important causes of anal fissures. The incidence of anal fissures accounts for about 20% among anorectal diseases.

[0009] At present, there are two main therapies for anal fissures, one is drug therapy and the other is surgery (lateral sphincterotomy). However, surgery is often associated with the risk of anal fistula. In order to relieve pain from bowel movements, the drug therapy is the first choice.

[0010] The drug therapy includes pain relief therapies, such as lidocaine gel, local injection of botulinum toxin, diltiazem hydrochloride and nitroglycerin cream. Diltiazem hydrochloride also shows a significant effect in the treatment of postoperative pain of hemorrhoids.

[0011] Oral tables of diltiazem hydrochloride were first marketed under the trade name Herbesser in Japan in February 1974, with the specifications of 30 mg and 60 mg, and then successively approved by the FDA and EMA, with the maximal specification of 120 mg. The improved new drugs of diltiazem hydrochloride, such as sustained-release capsules (with the maximal 197656.00028 specification of 420 mg) and injections (with the maximal specification of 50 mg), were also successively marketed mainly for the treatment of hypertension, angina, and arrhythmia. However, oral administration has shortcomings such as low cure rate and high side effects due to systemic distribution. Hence, the market is in an urgent need of a locally administered preparation of diltiazem hydrochloride with high local concentration and low systemic distribution, such that the side effects of the system can be reduced, and the cure rate can be improved.

[0012] At present, there is no semi-solid dosage form of diltiazem hydrochloride in the market of the United States. The reason lies in that diltiazem hydrochloride is very easily hydrolyzed into deacetyldiltiazem, and the efficacy of this hydrolysate will be reduced by 20%-40%. Moreover, diltiazem hydrochloride is readily oxidized. It is a huge challenge to develop a stable and qualified semi-solid dosage form of diltiazem hydrochloride.

[0013] Although semi-solid dosage form of diltiazem hydrochloride is not on the market, its off-label prescriptions have been widely available in retail pharmacies in the United States due to fewer side effects and good efficacy. In 2013, the FDA conducted unannounced inspections in retail pharmacies in the United States and found that 14 of the 36 prescriptions were below the USP standard, and 5 of the 12 pharmacies had an average efficacy lower than 90% of that claimed on the label, which indicate that the diltiazem hydrochloride has a definite efficacy but is difficult to keep stable, this is directly related to the instability of diltiazem hydrochloride in the semi-solid state. A need exists for a composition of diltiazem hydrochloride with improved efficacy and stability.

[0014] SUMMARY OF THE INVENTION

[0015] This patent document discloses a pharmaceutical composition of diltiazem hydrochloride featuring a simple formulation, readily available excipients, stable quality, and a rational process design suitable for industrial production. Notably, the composition requires no skin penetration enhancer.

[0016] An aspect of the patent document relates to a pharmaceutical composition of diltiazem hydrochloride. The composition includes excipients and a therapeutically effective amount of diltiazem hydrochloride, wherein the excipients comprise propylene glycol, tartaric acid ranging from 0.05% to 0.40% by weight in the composition, a gel matrix comprising one or both of povidone and hydroxypropyl cellulose, and optionally an antioxidant (e.g. tocopherol). 197656.00028

[0017] In some embodiments, the composition further contains benzoic acid, wherein the diltiazem hydrochloride ranges from 1% to 5%, the benzoic acid ranges from 0.1% to 5.0%, and the gel matrix ranges from 5% to 10% by weight in the composition. In some embodiments, the diltiazem hydrochloride ranges from 1% to 4%, the benzoic acid ranges from 0.25% to 0.75%, and the gel matrix ranges from 7.0% to 9.0% by weight in the composition.

[0018] In some embodiments, the diltiazem hydrochloride ranges from 1% to 5%, the tartaric acid ranges from 0.05% to 0.30%, and the gel matrix ranges from 5% to 10%. In some embodiments, the diltiazem hydrochloride ranges from 1% to 4%, the tartaric acid ranges from 0.10% to 0.25%, and the gel matrix ranges from 7.0% to 9.0%.

[0019] In some embodiments, the composition further contains tocopherol and benzoic acid.

[0020] In some embodiments, the gel matrix comprises hydroxypropyl cellulose. In some embodiments, the gel matrix comprises povidone. In some embodiments, the gel matrix comprises povidone and hydroxypropyl cellulose.

[0021] In some embodiments, the diltiazem hydrochloride ranges from 2% to 4% by weight in the composition. In some embodiments, the diltiazem hydrochloride is in an amount of 2% by weight in the composition. In some embodiments, the diltiazem hydrochloride is in an amount of 4% by weight in the composition.

[0022] In some embodiments, the propylene glycol is in an amount greater than 80% by weight in the composition.

[0023] In some embodiments, the excipients are selected so that at 25°C and 60% relative humidity, single unknown impurity is no more than 0.1%, impurity -F is no more than 1%, by weight in the composition within 3 months. In some embodiments, total impurities are no more than 1% by weight in the composition within 3 months. In some embodiments, the excipients are selected so that at 25°C and 60% relative humidity, single unknown impurity is no more than 0.2%, impurity -F is no more than 1.2%, total impurities are no more than 1.4% by weight in the composition within 6 months.

[0024] In some embodiments, the composition has pH ranging from 3.0 to 4.5 or from 3.2 to 4.2.

[0025] In some embodiments, the composition does not contain water. This is completely different from the conventional water-soluble gel. The composition exhibits excellent stability under a variety of extreme environments. 197656.00028

[0026] In some embodiments, in the pharmaceutical composition described above, based on percentage by weight, the diltiazem hydrochloride accounts for l%-5%, the benzoic acid accounts for 0.1%-3.0%, the gel matrix accounts for 5.0%-9.0%, and the balance is propylene glycol.

[0027] In some embodiments, in the pharmaceutical composition described above, based on percentage by weight, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.1%-2.0%, the gel matrix accounts for 7.0%-9.0%, and the balance is propylene glycol.

[0028] In some embodiments, in the pharmaceutical composition described above, based on percentage by weight, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.1%-1.0%, the gel matrix accounts for 7.0%-9.0%, and the balance is propylene glycol.

[0029] In some embodiments, in the pharmaceutical composition described above, based on percentage by weight, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.25%-0.75%, the gel matrix accounts for 7.0%-9.0%, and the balance is propylene glycol.

[0030] In some embodiments,, in the pharmaceutical composition described above, the gel matrix is hydroxypropyl cellulose.

[0031] Another aspect of the patent document provides a method for preparing the pharmaceutical composition disclosed herein. A further aspect provides a method of treating anal fissures and / or postoperative pain of anal fissures or hemorrhoids, comprising administering to a subject in need thereof the pharmaceutical composition disclosed herein.

[0032] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The embodiments below are merely intended to further illustrate the present invention but are not intended to limit the present invention. All techniques implemented based on the above description of the present invention shall be construed as falling within the scope of the present invention.

[0034] The composition disclosed herein addresses multiple development challenges commonly encountered in conventional formulations. First, diltiazem hydrochloride is highly unstable 197656.00028 and prone to hydrolysis and oxidation, both of which are accelerated in aqueous systems. Accordingly, the formulation cannot include water, necessitating the use of an organic solvent while maintaining the concentration of diltiazem hydrochloride. The inclusion of multiple solvents can create stability and compatibility issues.

[0035] Second, a suitable solvent must be identified that can dissolve both the thickener and diltiazem hydrochloride while maintaining stability of the drug substance. In some embodiments, the composition includes Povidone K90 and hydroxypropyl methylcellulose LXF.

[0036] Third, an appropriate preservative and / or pH regulator is required to enhance stability of the preparation. The agent must be compatible with the solvent.

[0037] Fourth, because diltiazem hydrochloride is readily oxidized, an antioxidant can be incorporated, provided it is soluble in the chosen solvent. The absence of water in the formulation markedly reduces oxidation.

[0038] Compared with conventional formulations, the composition disclosed herein offers one or more of the following advantages: it is entirely free of water, thereby improving the stability of diltiazem hydrochloride; it employs propylene glycol in high amount, far exceeding the typical <20% used in gels, while still keeping daily exposure (<3,000 mg) well below the FDA- approved topical limit of 6,113 mg; it incorporates benzoic acid and / or tartaric acid, which serve the dual function of preservative and pH regulator to further enhance stability; it provides a transparent, oil-free dosage form with no phase separation, increasing patient acceptability compared to creams and ointments; and it maintains a shelf life of at least one year at both room temperature and under refrigeration.

[0039] An aspect of the patent document provides a pharmaceutical composition of diltiazem hydrochloride. The composition comprises a therapeutically effective amount of the diltiazem hydrochloride, propylene glycol, tartaric acid , and a gel matrix, wherein the gel matrix comprises one or both of povidone and hydroxypropyl cellulose. Preferably, the compsoiton is in the form of a gel. Further, when the composition is in the form of a transparent gel, it is generally better accepted than creams or ointments and, lacking an oil phase, avoids the issue of phase separation. 197656.00028

[0040] Besides tartaric acid, one of more addiitoanl pH regulators can be included in the composition. Nonlimiting examples include acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethane-sulfonic acid, 2- hydroxy ethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid and ascorbic acid and any combination thereof.

[0041] In some embodiments, the composition further includes one or more antioxidants. Nonlimiting examples include tocopherol, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, sodium bisulfite, sodium metabisulfite, Sodium Formaldehyde Sulfoxylate, Sodium Ascorbate, propyl gallate, Sulfur Dioxide, Methionine, Vitamin E Polyethylene Glycol Succinate, ascorbyl palmitate, and any combination thereof. In some embodiments, the one or more antioxidants include tocopherol

[0042] In some embodiments, in the pharmaceutical composition described above, wherein the excipients include propylene glycol, one or both of tartaric acid and benzoic acid, and a gel matrix, which comprises one or both of povidone and hydroxypropyl cellulose. In some embodiments, based on percentage by weight, the diltiazem hydrochloride accounts for 1.0%- 5.0%, the benzoic acid accounts for 0. l%-5.0% or the tartaric acid accounts for 0.02%- 0.5%the gel matrix accounts for 5.0%- 10.0%, and the balance includes propylene glycol and optionally antioxidant.

[0043] Nonlimiting examples of the amount of diltiazem hydrochloride in the composition by weight includes about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, and any range between any two of the aforementioned values.

[0044] Nonlimiting examples of the amount of tartaric acid by weight in the composition include about 0.01%, about 0.02%, about 0.04%, about 0.05%, about 0.055%, about 0.06%, about 0.07%, about 0.08%, about 0.1%, about O.12%, about 0.15%, about 0.18%, about 0.20%, about O.22%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, and any range between any two of the aforementioned values. In some embodiments, the tartaric acid accounts for 0.02%-0.5%, 0.03%-0.5%, 0.04%-0.30%, 197656.00028

[0045] 0.05%-0.3%, 0.05%-0.5%, 0.05%-0.35%, 0.05%-0.25%, 0.10%-0.30%, 0.10%-0.25%, 0. Wo¬

[0046] 0.20%, 0.05%-0.40%, 0.05%-0.60%, 0.05%-l%, 0.05%-2%, 0.5%-3%, or l%-5%, by weight rn the composition.

[0047] In some embodiments, the composition comprises benzoic acid. Nonlimiting examples of the amount of benzoic acid in the composition by weight includes about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, and any range between any two of the aforementioned values. In some embodiments, benzoic acid ranges for 0.1%-5.0%, 0.1%-3.0%, 0.1%-2.0%, or 0.25%-0.75% by weight in the composition.

[0048] In some embodiments, based on percentage by weight in the composition, the diltiazem hydrochloride accounts for l%-5%, the benzoic acid accounts for 0.1%-5.0%, and the gel matrix accounts for 5%-10%. In some embodiments, based on percentage by weight, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.1%-3.0%, and the gel matrix accounts for 5.0%-9.0%. In some embodiments, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.1%-2.0%, and the gel matrix accounts for 7.0%-9.0%. In some embodiments, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.1%-1.0%, and the gel matrix accounts for 7.0%-9.0%. In some embodiments, the diltiazem hydrochloride accounts for l%-4%, the benzoic acid accounts for 0.25%-0.75%, and the gel matrix accounts for 7.0%-9.0%.

[0049] In some embodiments, based on percentage by weight in the composition, the gel matrix accounts for 4%-l 5%, 5%-10%, 5%-9%, or 7%-10%. Nonlimiting examples of the amount of the gel matrix in the composition include 3%, 4%, 5%, 8%, 10%, 12%, 14%, 20%, and any range between any two of the aforementioned values.

[0050] In some embodiments, the gel matrix comprises hydroxypropyl cellulose. In some embodiments, the gel matrix comprises povidone. In some embodiments, the gel matrix comprises povidone and hydroxypropyl cellulose.

[0051] In some embodiments, based on percentage by weight in the composition, the propylene glycol is greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%.

[0052] In some embodiments, the composition further comprises tocopherol. Nonlimiting examples of the amount of tocopherol by weight in the composition include about 0.01%, about 0.02%, 197656.00028 about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, and any range between any two of the aforementioned values. In some embodiments, the tocopherol accounts for 0.1% to 0.75% in the composition. In some embodiments, the tocopherol accounts for 0.25%-0.5% by weight in the composition. In some embodiments, the diltiazem hydrochloride accounts for l%-5%, the benzoic acid accounts for 0.1%-5.0%, and the gel matrix accounts for 5%-10%. Tartaric acid, when used in combination with tocopherol, provides much better chemical stability to the composition in comparison with other acids such as fumaric acid, lactic acid, malic acid and benzoic acid. In some embodiments, benzoic acid is less than 1%, less than 0.8%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.1%, or less than 0.05% by weight in the composition. In some embodiments, the composition is substantially free from benzoic acid.

[0053] The combination of tartaric acid and tocopherol, in comparison with the combinations of the antioxidant with other acids, surprisingly achieves a signifant improvement in starbilty (reducing the amounts of imprity-F, single impurity, and / or total impurities). In some embodiments, tartaric acid and tocopherol are in a weight ratio of 1 :4, 1 :3; 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, or any range between the aformetioned valuses (e.g. 1 :2-2: 1, 2:3-1 : 1, 1 : 1-1 :2, etc).

[0054] In some embodiments, the composition or gel has a pH of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, or any range between any two of the aforementioned values (e.g. 3.0-4.5, 3.0-4.2, 3.2-4.2, 3.2-4.0, 3.3-3.8, 3.3-3.5, etc.).

[0055] The composition disclosed herein also offers the advantage of a very low level of impurities. According to the USP, diltiazem hydrochloride tablets must contain 93.0%-107.0% of the labeled content, with any individual impurity not exceeding 0.5%. Deviations from these limits may reduce efficacy, while elevated levels of certain impurities can pose risks of toxicity or even carcinogenicity with long-term use. To address these concerns, the International Conference on Harmonization (ICH) issued guideline Q3B, which more strictly limits single impurities in finished drug products (<0.2%). In some embodiments, the composition disclosed herein is characterized by a 95.0%-105.0% content for diltiazem hydrochloride and <0.2% for any individual impurity. These internal control standards are stricter than those in the USP, thereby further minimizing the risk of reduced efficacy or safety issues over time.

[0056] Single impurity as used herein refers to any single unknown impurity. Deacetyldiltiazem is a well-known impurity where the acetyl group of diltiazem is removed. Total impurities 197656.00028 include all known and unknown impurities in the composition. The amount of an individual impurity or total impurities can be readily determined by established analytical methods.

[0057] In some embodiments, at 25°C and 60% relative humidity, deacetyldiltiazem in the pharmaceutical composition disclosed herein is no more than 0.50%, no more than 0.60%, no more than 0.70%, no more than 0.80%, no more than 0.85%, no more than 0.90%, no more than 1%, no more than 1.2%, no more than 1.5%, no more than 1.8%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5% by weight in the composition within a certain period of time. The period of time may be 1 month, 2 months, 3 months, 5 months, 6 months, 8 months, 12 months or 24 months.

[0058] In some embodiments, at 25°C and 60% relative humidity, the single impurity in the pharmaceutical composition disclosed herein is no more than 0.20%, no more than 0.25%, no more than 0.30%, no more than 0.35%, no more than 0.40%, no more than 0.50%, no more than 0.60%, no more than 0.70%, no more than 0.80%, no more than 0.85%, no more than 0.90%, no more than 1%, no more than 1.2%, no more than 1.5%, no more than 1.8%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5% by weight in the composition within a certain period of time. The period of time may be 1 month, 2 months, 3 months, 5 months, 6 months, 8 months, 12 months or 24 months.

[0059] In some embodiments, at 25°C and 60% relative humidity, the total impurities in the pharmaceutical composition disclosed herein is no more than no more than 0.40%, no more than 0.50%, no more than 0.60%, no more than 0.70%, no more than 0.80%, no more than 0.85%, no more than 0.90%, no more than 1%, no more than 1.1%, no more than 1.2%, no more than 1.3%, no more than 1.4%, no more than 1.5%, no more than 1.6%, no more than 1.8%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5% by weight in the composition within a certain period of time. The period of time may be 1 month, 2 months, 3 months, 5 months, 6 months, 8 months, 12 months or 24 months.

[0060] The following table illustrates a condition for determining the impurity level in the composition with HPLC. 197656.00028

[0061] In some embodiments, the composition disclosed herein contains less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 2%, or less than 1% glycerin or PEG (w / w). In some embodiments, the composition is substantially free from glycerin or PEG.

[0062] While the ranges of each components of the composition may vary, their total of course will be 100%. For example, in a composition where PEG accounts for at least 80%, diltiazem hydrochloride accounts for l%-5%, the benzoic acid when present accounts for 0.1%-5.0%, the tocopherol when present accounts for 0.25%-0.5%, and the gel matrix accounts for 5%- 10%, one would have recognized that the total of all the components must be 100%. It is not possible to have all components present in the composition at the maximum levels of their respective range.

[0063] In some embodiments, the pharmaceutical composition disclosed herein contains less than 5%, less than 2%, or less than 1% water (w / w). In some embodiments, the pharmaceutical composition disclosed herein is substantially free from water.

[0064] In some embodiments, the composition containing 2% or 4% diltiazem hydrochloride by weight is administered 1, 2 or 3 times or as needed / day. The amount of the composition administered each time is in a range of 0.1-2, 0.2-1.5, 0.3-1.2, or 0.5-1 g.

[0065] In the screening experiment of the present invention, the preparation method described in Example 7 is used, and the reagents of the same class are added sequentially.

[0066] In some embodiments, in the pharmaceutical composition described above, the pharmaceutical composition consists of 2% of the diltiazem hydrochloride, 89.5% of the propylene glycol, 0.5% of the benzoic acid, and 8.0% of the hydroxypropyl cellulose. 197656.00028

[0067] Various methods can be adopted to prepare the pharmaceutical composition described herein. In some embodiments, a manufacturing method includes the following steps:

[0068] 1) mixing propylene glycol accounting for 35%-70% of a prescribed amount with a gel matrix, stirring a resulting mixture for emulsification to obtain a matrix A;

[0069] 2) mixing a prescribed amount of tartaric acid and optionally benzoic acid with the balance of propylene glycol, and stirring a resulting mixture to obtain a solution B;

[0070] 3) adding a prescribed amount of diltiazem hydrochloride and optionally tocopherol to the solution B, stirring and heating a resulting mixture for dissolution to obtain a solution C; and

[0071] 4) adding the solution C to the matrix A for overall mixing in a homogeneous and uniform manner, and cooling a resulting mixture to room temperature to obtain the pharmaceutical composition.

[0072] In some embodiments, a manufacturing method includes the followings:

[0073] 1) Preparation of gel matrix of hydroxypropyl cellulose LXF. Propylene glycol is weighed out for later use; part of propylene glycol (35-70% of the prescribed amount) is poured into an emulsification pot; stirring is started; under a stirring state at a speed of 30-50 rpm, the prescribed amount of hydroxypropyl cellulose LXF is slowly added to the emulsification pot by vacuum pumping within no less than 5 minutes; a resulting mixture is stirred until complete and even dispersion; then, the mixture is heated 70-80°C to allow swelling of the gel matrix into transparency at a stirring speed of 30-50 rpm; and after full swelling, the matrix is cooled to 40-55°C for later use.

[0074] 2) Dissolution of tartaric acid and / or benzoic acid. The remaining part of propylene glycol is poured into an oil phase pot; and tartaric acid and / or benzoic acid is weighed and added to the oil phase pot, and then stirred and heated for dissolution, with a stirring speed of 40-55 rpm, a heating temperature of 40-50 °C, and a stirring duration of 10-60 min.

[0075] 3) Dissolution of diltiazem hydrochloride. Diltiazem hydrochloride is weighed and poured to the oil phase pot, and then stirred and heated till complete dissolution, with a stirring speed of 40-55 rpm, a heating temperature of 40-50°C, and a stirring duration of 20-30 min.

[0076] 4) Overall mixing. With the stirring speed (40-55 rpm) and temperature of the emulsification pot unchanged, a solution in the oil phase pot is added to the emulsification pot by vacuum pumping; with the emulsification pot in a vacuum state of 0.05—0.10 MPa, materials in the 197656.00028 emulsification pot are stirred and homogenized for 30-60 min at a rotating speed of 40-55 rpm and a homogenization speed of 40-55 rpm to allow even mixing of the materials; and finally, the materials are cooled to room temperature to obtain the composition as described. Also provided herein is a composition prepared according to the methods disclosed herein.

[0077] The present invention further provides an application of the pharmaceutical composition described above to preparation of drugs for treatment of anal fissures and postoperative pain of anal fissures or hemorrhoids.

[0078] Example 1 - Selection of different solvents

[0079] In order to allow the diltiazem hydrochloride in a dissolved state in a gel matrix, the solubility of the diltiazem hydrochloride in propylene glycol, glycerin, and polyethylene glycol was studied. Propylene glycol led to the highest solubility of up to 79 mg / ml. Therefore, propylene glycol was used as a basic solvent in the formulation of the present patent.

[0080] Propylene glycol has been widely used in gel preparations, with the common usage level not exceeding 20%. Considering that the formulation is preferably an anhydrous gel and required an additional solvent for supplement, the effect of propylene glycol on the stability of diltiazem was studied by taking propylene glycol as a basic solvent, glycerin and polyethylene glycol as solvent supplements, ethylparaben as a preservative, and povidone as a gel matrix. The compositions of formulations are shown in the table below. Because an anhydrous solvent is to be used, none of the existing anhydrous solvents is used at a level of more than 20%. It was observed that even if high-concentration propylene glycol was used, the safety and effectiveness in the later stage were not affected.

[0081] Table 1 - Investigation of different solvents 197656.00028

[0082] Appearance, viscosity, and skin feel are evaluated as shown in the table below.

[0083] Stability is evaluated as shown in the table below.

[0084] Table 3 Stability results for different solvents 197656.00028

[0085] ND: not detected; LOQ: 0.05%, the same below.

[0086] Conclusion: The above data show that with the propylene glycol, glycerin, and polyethylene glycol as solvents, the formulation containing polyethylene glycol resulted in the poorest stability, the formulation containing glycerin showed intermediate stability, and the formulation containing propylene glycol provided the best stability. Stability was further improved when the content of the propylene glycol is greater than 80%, but when this formulation (formulation 5) is stored for 1 M at room temperature, the single impurity content of 0.35% was higher than the internal control standard of 0.2%, which did not meet the requirements. Therefore, it is necessary to continue to optimize this formulation.

[0087] Example 2 - Selection of different thickeners

[0088] In Example 1, propylene glycol for optimal stability relative to glycerin and polyethylene glycol was examined. In this test, the thickener was optimized based on the formulation 5. Since different thickeners differ in viscosity, the content of thickener in the formulation may be different in the context of ensuring moderate viscosity, but will not affect the conclusion of the study. Thickeners such as carbopol, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC -Na), povidone PVP K90, and hydroxypropyl cellulose (HPC) were screened. The compositions of formulations are shown in the table below.

[0089] Table 4, Compositions of formulations with different thickeners

[0090] Appearance, viscosity, and skin feel are evaluated as shown in the table below. 197656.00028

[0091] Table 5. Evaluation of formulations with different thickeners

[0092] Conclusion: the carbopol was soluble in propylene glycol, but with rough appearance, and the viscosity and skin feel were no longer evaluated; the hydroxypropyl methylcellulose and the sodium carboxymethylcellulose were insoluble in propylene glycol, and the viscosity and skin feel were no longer evaluated; and the formulation 5 and formulation 10 showed a transparent and homogenous appearance with moderate viscosity, and thus were evaluated in stability, as shown in the table below.

[0093] Conclusion: hydroxypropyl cellulose (HPC) as the thickening matrix of the gel showed better stability than that of povidone (PVP K90) as the thickening matrix. However, after storage for 1 M at room temperature (25°C / 60% RH humidity), the single impurity accounted for 0.26% 197656.00028 which was greater than the internal control standard of 0.2%. Therefore, it was necessary to continue to optimize this formulation.

[0094] Example 3 - Screening among different preservatives

[0095] Example 2 demonstrates that the formulation taking the propylene glycol as a solvent and the hydroxypropyl cellulose as a thickener showed the best stability, but with the single impurity content that was still greater than the internal control standard of 0.2%. Two additional preservatives, namely, benzyl alcohol and benzoic acid were studied, for a contrast test, and the formulation compositions were shown in the table below.

[0096] Table 7, Screening of different preservative types

[0097] Table 8, Stability results for different preservatives 197656.00028

[0098] Conclusion: after the investigations on different types of preservatives, we were surprised to find that formulations containing benzoic acid were more stable than formulations containing ethylparaben and benzyl alcohol. After storage for 1 M at room temperature (25°C / 60%RH humidity), the single impurity accounted for 0.06% which was less than the internal control standard of 0.2%, and the hydrolyzed impurity Imp-F accounted for 0.24%, which was far less than the internal control standard of 3.0%. It was speculated that benzoic acid reduced the pH of the gel, which improved the stability of the preparation. Next, the stability of the preparations of the present patent was investigated with respect to other pH regulators, and the compositions of formulations was shown in the table below.

[0099] 197656.00028

[0100] Table 9, Compositions of formulations different pH regulators

[0101] Since citric acid and sodium dihydrogen phosphate were insoluble in propylene glycol, hydrochloric acid and tartaric acid were selected for a contrast study. The pH value and stability of each formulation studied were shown in the table below.

[0102] Table 10. Stability results for different pH regulators

[0103] It was observed that hydrochloric acid as the most conventional pH regulator did not meet relevant preparation requirements. The formulation with Benzoic acid and tartaric acid showed better stability than that with hydrochloric acid. 197656.00028

[0104] Example 4 - Screening of different contents of tartaric acid

[0105] Example 3 has demonstrated that the benzoic acid and tartaric acid greatly improves the stability of the formulation of the present patent. Select one pH regulator for further research. The content of tartaric acid was investigated in this test. The compositions of formulations were shown in the table below.

[0106] T able 11 Compositions of formulations with different contents of tartaric acid

[0107] Table 12 Summary of stability of formulations with different contents of tartaric acid

[0108] The formulations with 0.055%~0.22% of tartaric acid met the internal control standards (single impurity < 0.2%, Imp-F< 3.0%) after storage for 12 months at room temperature. Because single impurities and Imp-F significantly increased under room temperature, the effect of antioxidants was investigated on the basis of the formulation 15 in the next step. 197656.00028

[0109] Example 5 - Screening of different antioxidant types

[0110] Benzoic acid and tartaric acid exhibit comparable stability as pH regulators. Based on the screening of different types of antioxidants, benzoic acid was selected as the pH regulators .The present patent investigated the effects of butyl hydroxy anisole (BHA), dibutylhydroxytoluene (BHT) and DL-a-tocopherol on the stability of the preparation. The compositions of formulations were shown in the table below.

[0111] Table 13, Compositions of formulations with different antioxidant types

[0112] BHT was insoluble in propylene glycol and thus was no longer subject to stability investigation. The stability achieved by taking BHA and DL-a-tocopherol as antioxidants was evaluated as shown in the table below.

[0113] Table 14, Stability results for different antioxidant types

[0114] DL-a-tocopherol as the antioxidant was slightly superior to BHA for single impurity and total impurities. Next, the effect of different amounts of the antioxidant on the stability of the preparation was investigated.

[0115] Example 6 - Screening of the amounts of DL-a-tocopherol as antioxidant

[0116] DL-a-tocopherol as an antioxidant had been demonstrated to be superior to BHA. The obj ective 197656.00028 this test was to screen for an appropriate amount. The compositions of formulations were shown in the table below.

[0117] Table 15, Compositions of formulations with different vitamins E

[0118] Table 16. Summary of stability of formulations with different DL-a-tocopherol

[0119] It ws observed that 0.02%-0.5% of DL-a-tocopherol showed no significant effect on the stability of the preparation under refrigeration and at room temperature. At 60°C. higher concentrations of DL-a-tocopherol led to some improvement in stability. 197656.00028

[0120] Example 7 Stability of a 4% w / w diltiazem hydrochloride gel

[0121] The following formulation composition is to investigate the stability of a 4% w / w diltiazem hydrochloride gel.

[0122] Table 17. Formulation composition of 4% w / w diltiazem hydrochloride gel

[0123] Table 18. Summary of stability of formulation 25 and formulation26 197656.00028

[0124] Surprisingly, Formulation 24, when used in cobmiantion with antioxidant tocopherol, shows significantly better stability compared to Formulation 23, formulation 25, formulation 26 and formulation 27. It was tested under the condition of 6 months and / orl2 months at 25°C / 60% RH and 3 months under the accelerated condition of 40°C / 75%. This suggests the surprising effect from the combination of tartaric acid and tocopherol than from the combinations of tocopherol with other acids.

[0125] (1)A 4-Week Toxicity Study of Diltiazem Hydrochloride Gel by Repeated Anal canal and margin application to Beagle dogs with a 4-Week Recovery Period

[0126] Methods: A total of 50 Beagle Dogs (25 / sex) were randomly assigned to five groups (5 / sex / group) based on body weight and sex. Animals in Group 1 were dosed with Sodium Chloride Injection (0.9%) as the negative control group; animals in Group 2 were dosed with Diltiazem hydrochloride gel (Placebo) as the placebo control group; animals in Groups 3,4 and 5 were dosed with Diltiazem hydrochloride gel (formulation 24)at doses of 10.16, 19.80 or 39.76 mg / g (calculated based on DTZ) as the low, middle and high dose groups (with doses of 30.48, 59.40 and 119.28 mg / animal / animal / day, respectively). Animals were administered via anal canal and margin application, three times daily for 4-hour (+2 hours) intervals for 28 consecutive days with dose volume of 1 mL / dose for the negative control group and 1 g / animal / dose for Groups 2, 3, 4 and 5. The first 3 animals / sex / group were subjected to necropsy after the 4-week dosing period on Day 29, and the last 2 animals / sex / group were subj ected to necropsy at the end of the 4-week recovery period on Day 57. Parameters evaluated in toxicology study include clinical observation, body weight, food consumption, body 197656.00028 temperature, blood pressure, electrocardiogram, ophthalmoscopic examination, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis), tissue distribution, organ weights, macroscopic and histopathological examination. Toxicokinetic parameters of Diltiazem (DTZ) and its metabolites N-Desmethyl Diltiazem (DMeD) and O-Desacetyl Diltiazem (DAcD) in plasma were analyzed on Day 1 and Day 28.

[0127] Results:

[0128] No mortality or moribundity was observed in animals throughout the study. No test article- related abnormal changes were observed in food consumption, body temperature, blood pressure, electrocardiogram, ophthalmologic examinations, hematology, coagulation, clinical chemistry, urinalysis, organ weights and macroscopic observation in animals of any dose group.

[0129] Body weight: Decreases in body weight gain related to the test article were noted in male animals at 119.28 mg / animal / day on Day 21 to Day 28, with a decrease of 9.3% on Day 28.

[0130] Local Toxicity: During the study period, swelling, ulceration and scab at the administration site in clinical observation were noted in animals at all dose groups; small epidermal abscess (with incidences of 3 / 6 and 1 / 6, respectively) and hyperkeratosis / hypokeratosis (with incidences of 1 / 6 and 3 / 6, respectively) were observed microscopically at the administration site in animals at 59.40 and 119.28 mg / animal / day, and the severity of the lesions was minimal. After a 4-week recovery period, except for a minimal small epidermal abscess in a male animal in the middle dose group, the other lesions were completely recovered.

[0131] Table 19. Scoring Criteria for Skin Allergy

[0132] 197656.00028

[0133] (2) Buehler Test of Diltiazem Hydrochloride Gel in Guinea Pigs

[0134] Methods: A total of 60 Hartley guinea pigs (F: M = 1 : 1) were randomly divided into 4 groups. Groups 1 to 2 were 10 animals in each group, groups 3 to 4 were 20 animals in each group. Group 1 was given Sodium Chloride Injection (0.9%) as the negative control group; group 2 was given l-CHLORO-2,4-DINITROBENZENE as the positive control group, with a sensitizing concentration of 5 mg / mL and a challenge concentration of 0.5 mg / mL; group 3 was given test article (Diltiazem hydrochloride gel) and group 4 was given the placebo control article (Diltiazem hydrochloride gel Placebo). The dose volume was 0.5 mL / animal. Sensitization on Day 1, Day 8 and Day 15, challenge on Day 29. Since the animals in positive control group had a positive rate of > 15% after challenge, the second challenges were not performed. Animals of Groups 1 to 4 were observed administration site before the first sensitization (Day 1) and 1 h ± 5 min, 24 h ± 1 h after drug remove of each sensitization, before challenge and 24 h ± 1 h, 48 h ± 1 h after drug remove of challenge, for erythema, oedema and other abnormal reactions of skin. The erythema and oedema after challenge were scored. 197656.00028

[0135] Table 20. Individual Data of Administration Area Observation after Sensitization 197656.00028

[0136] Note: Group 1 is negative control group, Group 2 is positive control group, Group 3 is test article group, Group 4 is placebo control article group. After administration indicates after drug removed. “A” indicate erythema, “B”indicates oedema, “C” indicates other symptoms. indicates no relevant symptom, “+” indicates relevant symptom was observed, “77” indicates Ulceration, “78” indicates Scab.

[0137] Table 21, Administration Area Observation after Challenge and Score 197656.00028 197656.00028

[0138] Note: Group 1 is negative control group, Group 2 is positive control group, Group 3 is test article group, Group 4 is placebo control article group. After administration indicates after drug removed. “A” indicate erythema, “B” indicates oedema, “C” indicates other symptoms. “+” indicates the reaction was observed, indicates no relevant symptom, “0” indicates no erythema / oedema, “1” indicates slight visible erythema / mild oedema, “2” indicates moderate erythema / oedema, “3” indicates severe erythema / oedema, “4” indicates oedematous erythema. “NA” indicates not scored.

[0139] Conclusion: Under the conditions of this study, repeated skin application of Diltiazem hydrochloride gel to Hartley guinea pigs did not cause skin sensitization, which was consistent with the results of Diltiazem hydrochloride gel Placebo.

[0140] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described. Rather, the scope of the present invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific portion of the invention, and may result from a different combination of described portions, or that other un-described alternate embodiments may be available for a portion, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

197656.00028CLAIMS1. A pharmaceutical composition in the form of a gel, comprising excipients and a therapeutically effective amount of diltiazem hydrochloride, wherein the excipients comprise: propylene glycol, tartaric acid ranging from 0.05% to 0.40% by weight in the composition, a gel matrix comprising one or both of povidone and hydroxypropyl cellulose, and optionally tocopherol.

2. The pharmaceutical composition of claim 1, further comprising benzoic acid, wherein the diltiazem hydrochloride ranges from 1% to 5%, the benzoic acid ranges from 0.1% to 5.0%, and the gel matrix ranges from 5% to 10% by weight in the composition.

3. The pharmaceutical composition of any one of claims 1-2, wherein the diltiazem hydrochloride ranges from 1% to 4%, the benzoic acid ranges from 0.25% to 0.75%, and the gel matrix ranges from 7.0% to 9.0% by weight in the composition.

4. The pharmaceutical composition of any one of claims 1-3, wherein the diltiazem hydrochloride ranges from 1% to 5%, the tartaric acid ranges from 0.05% to 0.30%, and the gel matrix ranges from 5% to 10%, by weight in the composition.

5. The pharmaceutical composition of claim 1, wherein the diltiazem hydrochloride ranges from 1% to 4%, the tartaric acid ranges from 0.10% to 0.25%, and the gel matrix ranges from 7.0% to 9.0%, by weight in the composition.

6. The pharmaceutical composition of any one of claims 1 and 5, further comprising tocopherol and benzoic acid.

7. The pharmaceutical composition of any one of claims 1-6, wherein the gel matrix comprises hydroxypropyl cellulose.

8. The pharmaceutical composition of any one of claims 1-7, wherein the gel matrix comprises povidone.

9. The pharmaceutical composition of any one of claims 1-8, wherein the gel matrix comprises povidone and hydroxypropyl cellulose.197656.0002810. The pharmaceutical composition of any one of claims 1-9, wherein the diltiazem hydrochloride ranges from 2% to 4% by weight in the composition.

11. The pharmaceutical composition of any one of claims 1-10, wherein the diltiazem hydrochloride is in an amount of 2% or 4% by weight in the composition.

12. The pharmaceutical composition of any one of claims 1-11, wherein the propylene glycol is in an amount greater than 80% by weight in the composition.

13. The pharmaceutical composition of any one of claims 1-12, wherein the excipients are selected so that at 25°C and 60% relative humidity, single unknown impurity is no more than 0.1%, deacetyldiltiazem is no more than 1%, by weight in the composition within 3 months.

14. The pharmaceutical composition of any one of claims 1-13, wherein the excipients are selected so that total impurities are no more than 1% by weight in the composition within 3 months.

15. The pharmaceutical composition of any one of claims 1-14, wherein the excipients are selected so that at 25°C and 60% relative humidity, single unknown impurity is no more than 0.2%, deacetyldiltiazem is no more than 1.2%, total impurities are no more than 1.4% by weight in the composition within 6 months.

16. The pharmaceutical composition of any one of claims 1-15, which has a pH ranging from 3.2 to 4.2.

17. The pharmaceutical composition of any one of claims 1-16, where glycerin or PEG is present in an amount of less than 20% by weight in the composition.

18. The pharmaceutical composition of any one of claims 1-17, which is substantially free from water.

19. A method for preparing the pharmaceutical composition of any one of claims 1-18, comprising the following steps:1) mixing propylene glycol accounting for 35%-70% of a prescribed or predetermined amount with a gel matrix, heating and stirring a resulting mixture for emulsification to obtain a matrix A;2) mixing a prescribed or predetermined amount of tartaric acid with the rest of the propylene glycol, and stirring a resulting mixture to obtain a solution B;3) adding a prescribed or predetermined amount of diltiazem hydrochloride and optionally tocopherol to the solution B, stirring and heating a resulting mixture for dissolution to obtain a solution C; and197656.000284) adding the solution C to the matrix A for overall mixing in a homogeneous and uniform manner, and cooling a resulting mixture to room temperature to obtain the pharmaceutical composition.

20. A method of treating anal fissures and / or postoperative pain of anal fissures or hemorrhoids, comprising administering to a patient in need thereof the pharmaceutical composition of any one of claims 1-18.

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