Application of AZD2423 in preparation of medicine for treating solid tumors

Abstract

The invention relates to the technical field of medicines, discloses application of AZD2423 in preparation of a medicine for treating solid tumors, and aims to provide a new technical choice for solid tumor treatment. The solid tumor can be selected from at least one of peritoneal tumor, lung cancer, prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer and colorectal cancer; in the medicine, the AZD2423 or the pharmaceutically acceptable salt of the AZD2423 can be used as the only active ingredient of the medicine; experimental results show that the application has remarkable inhibitory activity on patient-derived tumor-like cell cluster (PTC) models of various solid tumors; in peritoneal tumor and lung cancer models, the inhibition effect of the compound is superior to that of a positive control drug paclitaxel, and the effect of the compound in other tumor models is equivalent to that of paclitaxel. The invention provides a new scheme with a good application prospect for solid tumor treatment.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to the use of AZD2423 in preparing medicines for treating solid tumors. Background Art

[0002] Malignant tumors are one of the major diseases that seriously endanger human health. They are formed by the malignant proliferation of cells in the body and invasion of surrounding tissues or metastasis to other organs through the circulatory system. At present, the clinical treatment of solid tumors is still mainly based on traditional methods such as surgical resection, radiotherapy and chemotherapy. In recent years, although emerging therapies such as targeted therapy and immunotherapy have made significant progress, existing treatment options generally have certain limitations. For example, the treatment cost of some drugs is high, or they produce strong toxic side effects on the body while killing tumor cells. These factors limit their widespread application. Therefore, the development of new anti-tumor drugs that are both safe and effective has always been an important topic in the medical field.

[0003] "Repurposing old drugs" is a key strategy in drug development, aiming to discover new therapeutic indications from existing, clinically proven drugs. This strategy has gained increasing attention due to advances in biomedical technology, offering new insights into combating complex diseases such as cancer.

[0004] In the tumor microenvironment, the chemokine receptor signaling pathway plays a key role. After some chemokine receptors are activated, they can recruit immunosuppressive cells into the tumor tissue, thereby helping tumor cells evade the surveillance and attack of the immune system. At the same time, this signaling pathway is also involved in regulating the formation of tumor blood vessels, providing conditions for tumor growth and metastasis. Based on this, the development of inhibitors targeting specific chemokine receptors to block the above-mentioned pathological processes has become a direction of anti-tumor drug research. AZD2423 is such an inhibitor of the chemokine receptor CCR2, which was originally developed for the treatment of inflammatory diseases. Although AZD2423 showed acceptable safety in early Phase I clinical trials, it failed to show the expected therapeutic effect in subsequent clinical studies for inflammatory indications. In this context, the potential application value of this compound in other therapeutic areas, especially in anti-tumor treatment, has not been clearly recognized and reported. Summary of the Invention

[0005] The technical problem to be solved by the present invention is that some existing tumor treatment drugs have serious toxic side effects and high costs. Therefore, it is necessary to provide an alternative or supplementary treatment drug with good safety and effective against various solid tumors.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides the use of AZD2423 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating solid tumors.

[0008] In some embodiments, the solid tumor is at least one selected from the group consisting of peritoneal tumors, lung cancer, prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer, and colorectal cancer.

[0009] In some embodiments, the solid tumor is a peritoneal tumor or lung cancer.

[0010] In some embodiments, the solid tumor is at least one selected from the group consisting of prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer, and colorectal cancer.

[0011] In some embodiments, the dosage form of the drug is capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

[0012] In a further embodiment, in the medicament, AZD2423 or a pharmaceutically acceptable salt thereof is the only pharmaceutically active ingredient.

[0013] In a further embodiment, the drug is used to treat patients with solid tumors that have been screened using a patient-derived tumor-like cell cluster model as being responsive to the drug.

[0014] A second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of AZD2423 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is used for treating solid tumors.

[0015] In some embodiments, the solid tumor is at least one selected from the group consisting of peritoneal tumors, lung cancer, prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer, and colorectal cancer.

[0016] In a further embodiment, the composition is prepared as a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention provides a new use of the compound AZD2423 and a pharmaceutically acceptable salt thereof in the treatment of solid tumors. AZD2423 is an inhibitor of the chemokine receptor CCR2. The signaling axis formed by CCR2 and its ligand CCL2 participates in tumor invasion and metastasis by recruiting immunosuppressive cells (e.g., monocytes that can differentiate into tumor-associated macrophages) and promoting angiogenesis in the tumor microenvironment. AZD2423, as a CCR2 inhibitor, was previously used in clinical studies of inflammatory diseases but did not achieve the expected anti-inflammatory effect. The present invention found that the compound exhibited significant inhibitory activity against a variety of solid tumors, an effect that would have been unforeseeable for a compound that had failed in clinical development for other indications.

[0019] The technical effects of the present invention were verified using a patient-derived tumor-like cell cluster (PTC) model containing multiple solid tumor sources. The model maintained the original tumor microenvironment including fibroblasts and immune cells in vitro. The experimental results showed:

[0020] AZD2423 showed inhibitory effects on PTCs in eight different solid tumors, including peritoneal, lung, prostate, ovarian, stomach, thyroid, liver, and colorectal tumors, as measured by a reduction in PTC area and / or cellular ATP content. This confirms the broad spectrum of AZD2423's anti-tumor effects.

[0021] 2. In the tumor models tested, the inhibitory effect of AZD2423 at concentrations of 10-100 μM was comparable to that of the positive control drug paclitaxel at 0.75 μM. In peritoneal and lung cancer PTC models, AZD2423 exhibited statistically superior inhibitory effects on PTC area or activity compared to paclitaxel at specific concentrations.

[0022] 3. In view of the safety characteristics of AZD2423 shown in Phase I clinical trials, the present invention provides a drug application that has anti-solid tumor activity and may have a safety profile different from traditional cytotoxic chemotherapy drugs, providing a new technical option for the treatment of solid tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a schematic diagram of the normalized area ratio of peritoneal tumor PTCs on day 7 after drug treatment to that without treatment in Example 1 of the present invention;

[0024] Figure 2 This is a schematic diagram of the normalized results of ATP signal values of peritoneal tumor PTCs after 7 days of drug treatment in Example 1 of the present invention;

[0025] Figure 3This is a schematic diagram of the normalized area ratio of lung cancer PTCs on day 7 after drug treatment to that of untreated PTCs in Example 2 of the present invention;

[0026] Figure 4 This is a schematic diagram of the normalized results of ATP signal values of lung cancer PTCs after 7 days of drug treatment in Example 2 of the present invention;

[0027] Figure 5 This is a schematic diagram of the normalized area ratio of prostate cancer PTCs on day 7 after drug treatment to that of untreated PTCs in Example 3 of the present invention;

[0028] Figure 6 This is a schematic diagram of the normalized results of ATP signal values of prostate cancer PTCs after 7 days of drug treatment in Example 3 of the present invention;

[0029] Figure 7 This is a schematic diagram of the normalized area ratio of ovarian cancer PTCs on day 7 after drug treatment to that of untreated cells in Example 4 of the present invention;

[0030] Figure 8 This is a schematic diagram of the normalized results of ATP signal values of ovarian cancer PTCs after 7 days of drug treatment in Example 4 of the present invention;

[0031] Figure 9 This is a schematic diagram of the normalized area ratio of gastric cancer PTCs on day 7 after drug treatment to that without treatment in Example 5 of the present invention;

[0032] Figure 10 This is a schematic diagram of the normalized results of ATP signal values of gastric cancer PTCs after 7 days of drug treatment in Example 5 of the present invention;

[0033] Figure 11 This is a schematic diagram of the normalized area ratio of thyroid cancer PTCs on the 7th day after drug treatment to that of untreated cells in Example 6 of the present invention;

[0034] Figure 12 This is a schematic diagram of the normalized results of ATP signal values of thyroid cancer PTCs after 7 days of drug treatment in Example 6 of the present invention;

[0035] Figure 13 This is a schematic diagram of the results of normalizing the area ratio of liver cancer PTCs on the 7th day after drug treatment to that of untreated patients in Example 7 of the present invention;

[0036] Figure 14 This is a schematic diagram of the normalized ATP signal values of liver cancer PTCs after 7 days of drug treatment in Example 7 of the present invention;

[0037] Figure 15This is a schematic diagram of the normalized area ratio of colorectal cancer PTCs on day 7 after drug treatment to that without treatment in Example 8 of the present invention;

[0038] Figure 16 This is a schematic diagram of the normalized results of ATP signal values of colorectal cancer PTCs after 7 days of drug treatment in Example 8 of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described in detail below. However, it will be understood by those skilled in the art that the preparation examples and embodiments described below are intended to illustrate the present invention, rather than to limit the scope of the present invention.

[0040] The experimental materials and reagents used in the examples of the present invention were all commercially available. AZD2423 (CAS No. 1229603-37-5) was purchased from MCE (MedChemExpress); paclitaxel (CAS No. 33069-62-4) was purchased from Selleck; and Genex Health 100-well plates were purchased from Beijing Cornerstone Biotechnology Co., Ltd. The 3D Cell Viability Assay kit was purchased from Promega Biotechnology Co., Ltd.

[0041] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of AZD2423 and is biologically or otherwise suitable. It may be formed from inorganic or organic acids. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0042] The pharmaceutical composition of the present invention comprises the active ingredient AZD2423 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The excipients are conventional pharmaceutical materials that are harmless to the recipient and do not affect the biological activity of the active ingredient. Depending on the route of administration and dosage form, the excipients may be selected from fillers, diluents, binders, wetting agents, disintegrants, lubricants, solvents, cosolvents, pH regulators, or preservatives. For example, fillers may be selected from starch, lactose, sucrose, glucose, mannitol, or microcrystalline cellulose; binders may be selected from sodium carboxymethylcellulose, alginates, gelatin, or polyvinylpyrrolidone; disintegrants may be selected from cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose; lubricants may be selected from magnesium stearate; and solvents may be selected from water for injection, ethanol, or propylene glycol.

[0043] As used herein, the term "therapeutically effective amount" refers to an amount of AZD2423 or a pharmaceutically acceptable salt thereof that is capable of inhibiting, regressing, or alleviating solid tumors, or delaying tumor progression. The specific therapeutically effective amount depends on factors such as the route of administration, dosage form, patient age and weight, and the specific type and severity of the solid tumor being treated. As a non-limiting example, for an adult (70 kg body weight), the daily dose of AZD2423 or a pharmaceutically acceptable salt thereof may range from 1 mg to 2000 mg. The dose may be administered as a single dose or as divided doses over multiple days.

[0044] Preparation Example 1: AZD2423 Tablets

[0045] Mix 100g of AZD2423, 150g of lactose, 50g of microcrystalline cellulose, and 40g of starch. Prepare a soft base with an appropriate amount of 10% polyvinylpyrrolidone in ethanol, granulate through a 16-mesh sieve, and dry at 60°C. Add 5g of magnesium stearate, mix thoroughly, and compress into tablets containing 100mg of active ingredient per tablet.

[0046] Preparation Example 2: AZD2423 Capsules

[0047] 100 g of AZD2423 and 200 g of starch were mixed evenly, passed through a 100-mesh sieve, and then filled into hard capsules using a capsule filling machine to obtain capsules containing 100 mg of active ingredient per capsule.

[0048] Preparation Example 3: AZD2423 Injection

[0049] Weigh 10g of AZD2423 and dissolve it in an appropriate amount of propylene glycol. Add water for injection to 1000mL and stir to dissolve. Sterilize the solution by filtration through a 0.22μm filter membrane. Dispense into ampoules, seal them, and sterilize them to obtain an injection solution containing 10mg of the active ingredient per mL.

[0050] Data statistics description:

[0051] The data in the figures are presented as mean ± standard deviation. ns indicates no significant difference between the two groups (P ≥ 0.05) after statistical analysis; * or # indicates a significant difference between the two groups (P < 0.05); ## indicates a significant difference between the two groups (P < 0.01); *** or ### indicates a significant difference between the two groups (P < 0.001); **** or #### indicates a significant difference between the two groups (P < 0.0001).

[0052] Example 1: Inhibitory effect of AZD2423 on peritoneal tumor-derived PTCs

[0053] (1) Grouping and treatment: After digestion, peritoneal tumor sample #1 was cultured in a PTC-specific culture medium to obtain patient-derived tumor-like cell clusters (PTCs). PTCs with a diameter greater than 40 μm were selected and inoculated in a 100-well plate at a density of 30-50 PTCs per well. The experimental groups were as follows: negative control group (containing only culture medium), paclitaxel group (0.75 μM), AZD2423-1 group (20 μM), and AZD2423-2 group (10 μM). Three replicate wells were set up for each group. The corresponding drug was added on the day of inoculation and the treatment was continued for seven consecutive days.

[0054] (2) PTCs area assessment: The two-dimensional projection area of PTCs in each group was measured using a microscope and analysis software before drug treatment (day 0) and after treatment (day 7). The average area ratio of PTCs in each group on day 7 relative to that on day 0 was calculated, and the ratio was normalized to the negative control group. The results are shown in Figure 2. Figure 1 As shown, compared with the negative control group, the normalized area ratios of the paclitaxel (0.75 μM), AZD2423 (10 μM), and AZD2423 (20 μM) groups were all reduced. The inhibitory effect of the AZD2423 (10 μM) group was not statistically different from that of the paclitaxel group. The normalized area ratio of the AZD2423 (20 μM) group was significantly lower than that of the paclitaxel group.

[0055] (3) PTCs viability assessment: Seven days after drug treatment, the chemiluminescent signal value corresponding to the ATP concentration in each well was detected using the CellTiter-Glo detection kit. The signal value reflects the number of viable cells. The signal value of each treatment group was normalized relative to the negative control group. The results are shown in Figure 2. Figure 2 As shown in Figure 2, compared with the negative control group, the normalized ATP signal values of all drug-treated groups were significantly reduced. There was no statistical difference in the ATP signal values of the AZD2423 (10 μM and 20 μM) groups and the ATP signal values of the paclitaxel group.

[0056] Example 2: Inhibitory effect of AZD2423 on lung cancer-derived PTCs

[0057] (1) Grouping and treatment: The experimental steps were the same as in Example 1(1), and the tumor sample was lung cancer sample #2.

[0058] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 3 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 (10 μM and 20 μM) group were reduced. There was no statistically significant difference between the normalized area ratios of the AZD2423 (10 μM and 20 μM) group and the paclitaxel group.

[0059] (3) PTCs activity evaluation: The experimental and data processing steps are the same as those in Example 1 (3). Figure 4 As shown in Figure 3, compared with the negative control group, the normalized ATP signal values of all drug-treated groups were significantly reduced. The normalized ATP signal values of the AZD2423 (10 μM and 20 μM) groups were significantly lower than those of the paclitaxel group.

[0060] Example 3: Inhibitory effect of AZD2423 on prostate cancer-derived PTCs

[0061] (1) Grouping and treatment: The experimental steps were the same as in Example 1(1), and the tumor sample was prostate cancer sample #3.

[0062] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 5 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 (10 μM and 20 μM) group were reduced, and there was no statistically significant difference between the AZD2423 concentration groups and the paclitaxel group.

[0063] (3) PTCs activity assessment: The experimental and data processing steps are the same as those in Example 1 (3) to reflect the activity of prostate cancer PTCs. Figure 6 As shown, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 (10 μM and 20 μM) group were significantly decreased.

[0064] Example 4: Inhibitory effect of AZD2423 on ovarian cancer-derived PTCs

[0065] (1) Grouping and treatment: The experimental steps were the same as in Example 1 (1), except that the tumor sample was ovarian cancer sample #4. The experimental groups were: negative control group, paclitaxel group (0.75 μM), and AZD2423 group (100 μM).

[0066] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 7 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 group were both reduced, and there was no statistically significant difference between the two groups.

[0067] (3) PTCs activity assessment: The experimental and data processing steps are the same as those in Example 1 (3), which are used to reflect the activity of ovarian cancer PTCs. Figure 8 As shown in the figure, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 group were significantly reduced, and there was no statistically significant difference between the two groups.

[0068] Example 5: Inhibitory effect of AZD2423 on gastric cancer-derived PTCs

[0069] (1) Grouping and treatment: The experimental steps were the same as in Example 1 (1), except that the tumor sample was gastric cancer sample #5. The experimental groups were: negative control group, paclitaxel group (0.75 μM), and AZD2423 group (20 μM).

[0070] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 9 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 group were both reduced, and there was no statistically significant difference between the two groups.

[0071] (3) PTCs activity evaluation: The experimental and data processing steps are the same as those in Example 1 (3). Figure 10 As shown in the figure, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 group were significantly reduced, and there was no statistically significant difference between the two groups.

[0072] Example 6: Inhibitory effect of AZD2423 on thyroid cancer-derived PTCs

[0073] (1) Grouping and treatment: The experimental steps were the same as in Example 1 (1), except that the tumor sample was thyroid cancer sample #6. The experimental groups were: negative control group, paclitaxel group (0.75 μM), and AZD2423 group (20 μM).

[0074] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 11 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 group were both reduced, and there was no statistically significant difference between the two groups.

[0075] (3) PTCs activity assessment: The experimental and data processing steps are the same as those in Example 1 (3), used to reflect the activity of thyroid cancer PTCs. Figure 12 As shown in the figure, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 group were significantly reduced, and there was no statistically significant difference between the two groups.

[0076] Example 7: Inhibitory effect of AZD2423 on liver cancer-derived PTCs

[0077] (1) Grouping and treatment: The experimental steps were the same as in Example 1 (1), except that the tumor sample was liver cancer sample #7. The experimental groups were: negative control group, paclitaxel group (0.75 μM), and AZD2423 group (20 μM).

[0078] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 13 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 group were both reduced, and there was no statistically significant difference between the two groups.

[0079] (3) PTCs activity evaluation: The experimental and data processing steps are the same as those in Example 1 (3). Figure 14 As shown in the figure, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 group were significantly reduced, and there was no statistically significant difference between the two groups.

[0080] Example 8: Inhibitory effect of AZD2423 on colorectal cancer-derived PTCs

[0081] (1) Grouping and treatment: The experimental steps were the same as in Example 1 (1), and the tumor sample was colorectal cancer sample #8. The experimental groups were: negative control group, paclitaxel group (0.75 μM), and AZD2423 group (20 μM).

[0082] (2) PTCs area evaluation: The experimental and data processing steps are the same as those in Example 1 (2). Figure 15 As shown in the figure, compared with the negative control group, the normalized area ratios of the paclitaxel group and the AZD2423 group were both reduced, and there was no statistically significant difference between the two groups.

[0083] (3) PTCs activity evaluation: The experimental and data processing steps are the same as those in Example 1 (3). Figure 16 As shown in Figure 3, compared with the negative control group, the normalized ATP signal values of the paclitaxel group and the AZD2423 group were reduced to less than 50%, and there was no statistically significant difference between the two groups.

[0084] The results of Examples 1-8 collectively demonstrate that AZD2423, as a single active ingredient, exhibits inhibitory activity against PTC models of various solid tumors originating from peritoneal, lung, prostate, ovary, stomach, thyroid, liver, and colorectal sources. In some tumor models, AZD2423 demonstrated superior inhibitory efficacy compared to the positive control drug, paclitaxel, on specific assay parameters; in other tumor models, its inhibitory efficacy was comparable to that of paclitaxel.

[0085] The foregoing description is merely a specific embodiment of the present invention, and the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be readily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. Use of AZD2423 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating solid tumours.

2. The use according to claim 1, characterized in that The solid tumor is selected from at least one of peritoneal tumors, lung cancer, prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer and colorectal cancer.

3. The use according to claim 2, characterized in that The solid tumor is a peritoneal tumor or lung cancer.

4. The use according to claim 2, characterized in that The solid tumor is selected from at least one of prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer and colorectal cancer.

5. The use according to any one of claims 1 to 4, characterized in that The dosage form of the drug is capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

6. The use according to claim 5, characterized in that In the medicament, AZD2423 or a pharmaceutically acceptable salt thereof is the only active pharmaceutical ingredient.

7. The use according to claim 5, characterized in that The drug is used to treat patients with solid tumors that have been screened as effective using a patient-derived tumor-like cell cluster model.

8. A pharmaceutical composition, characterized in that The composition comprises a therapeutically effective amount of AZD2423 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, and is used for treating solid tumors.

9. The pharmaceutical composition according to claim 8, characterized in that The solid tumor is selected from at least one of peritoneal tumors, lung cancer, prostate cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer and colorectal cancer.

10. The pharmaceutical composition according to claim 8 or 9, characterized in that The composition is prepared into capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

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