Application of itraconazole in preparation of medicine for treating Parkinson's disease

Abstract

The invention belongs to the technical field of medicines, and discloses application of itraconazole shown in a formula (I) in preparation of a medicine for treating and / or preventing Parkinson's disease. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a new medical use of itraconazole represented by formula (I), specifically the use of itraconazole in treating and / or preventing Parkinson's disease.

[0002] Background Art

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Its main clinical manifestations are movement disorders, including resting tremor, bradykinesia, muscle rigidity, posture changes, gait instability, etc. In addition, most PD patients are accompanied by a variety of non-motor symptoms, such as cognitive decline, depression, anxiety, autonomic dysfunction (such as constipation), sleep disorders, orthostatic hypotension, urinary dysfunction, etc. The typical pathological hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta, which induces dopamine depletion in the striatum, Lewy bodies formed by misfolding and abnormal aggregation of α-synuclein (α-synuclein, α-Syn), and excessive activation of glial cells in the brain. At present, the number of PD patients in my country ranks first in the world, about 3.1 million. It is estimated that by 2030, the number of PD patients in my country will increase to 5 million, accounting for more than 50% of the total number of PD patients in the world. As PD progresses, the quality of life of patients is seriously affected and the burden on family and society increases. Therefore, it is particularly important to develop more safe and effective drugs for the treatment of PD that can be used clinically.

[0004] Clinically, the treatment of PD is mainly aimed at the treatment of motor symptoms, that is, increasing the concentration of dopamine in the brain or stimulating dopamine receptors, such as levodopa, dopamine receptor agonists, MAO-B inhibitors, COMT inhibitors, amantadine, anticholinergic drugs, etc., with levodopa replacement therapy as the main treatment; secondly, the treatment of non-motor symptoms related to PD, such as donepezil for the treatment of cognitive impairment, antidepressant fluoxetine, antipsychotic clozapine, clonazepam for the treatment of sleep disorders, drugs for the treatment of urinary and autonomic nervous system disorders, etc.; neuroprotective drugs such as vitamin E, coenzyme Q10, etc. The above-mentioned therapeutic drugs often cause serious adverse reactions, such as nausea, drowsiness, edema, addiction, hallucinations, hyperactivity, granulocytopenia, pulmonary and heart valve fibrosis, etc., and the medication should be used with caution, and clinical monitoring is required when necessary. In addition, PD patients usually have multiple symptoms and often use combined treatments, which are more likely to cause interactions between drugs and cause serious toxic side effects. Therefore, it is very necessary to develop new drugs for the treatment of PD.

[0005] The strategy of repurposing old drugs is widely used in the development of new drugs for PD. For example, adamantane was the first antiviral drug used to inhibit influenza virus. Researchers found that adamantane can promote dopamine release and reduce dopamine loss, and it has become a basic clinical drug for the treatment of PD. Therefore, repurposing old drugs can help improve the current situation of insufficient clinical PD medication. Itraconazole is an antifungal drug widely used in clinical practice and a key member of the triazole antifungal drug family. It is on the World Health Organization's list of essential medicines and is one of the most important drugs in the basic health system. Its safety is beyond doubt. The inventor of this patent used a variety of experiments to prove that itraconazole can significantly improve the movement disorders of PD mice, and its efficacy is equivalent to that of the positive drug levodopa. Summary of the invention

[0006] The technical problem solved by the present invention is to provide application of itraconazole in preparing a drug for treating and / or preventing PD.

[0007] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0008] The first aspect of the technical solution of the present invention is to provide the use of itraconazole and its pharmaceutically acceptable salts as shown in formula (I) in the preparation of drugs for treating and / or preventing PD.

[0009]

[0010] To verify the technical solution of the present invention, the present invention provides two animal models. The first animal model is a rotenone-induced PD animal model: Rotenone (Rot) is a natural organic insecticide that is lipophilic and can penetrate the blood-brain barrier. It has a strong and extensive inhibitory effect on the activity of complex I of the respiratory chain of brain tissue mitochondria. Although rotenone has no selectivity in inhibiting the activity of complex I, it can selectively cause degeneration of the substantia nigra-striatum DA system, which may be related to the sensitivity of DA neurons to oxidative stress. This model can well simulate PD-related characteristics in terms of pathology, biochemistry, pathogenic mechanism, behavior, etc.

[0011] The second animal model of the present invention is an α-synuclein (α-synuclein, α-Syn) (A53T) transgenic mouse with a pathogenesis very similar to that of humans. The mouse prion protein promoter regulates the expression of the human α-Syn A53T mutation, which is located in the amino terminal region of α-Syn, leading to SNCA gene mutation, causing α-Syn to aggregate into Lewy bodies, hindering dopamine metabolism and the normal function of neurons, leading to neuronal death. Homozygous mice may begin to show behavioral abnormalities at 8-9 months of age, and most mice show typical PD phenotypes such as tremors and hunched backs at 14-15 months of age. Its onset is induced by genetic susceptibility, which is very similar to the manifestations of human PD and is often used as a PD animal model.

[0012] The present invention uses the above two models to evaluate the activity of itraconazole in treating PD.

[0013] The second aspect of the technical solution of the present invention is to provide a pharmaceutical composition for use in preparing a drug for treating and / or preventing PD, characterized in that the pharmaceutical composition comprises itraconazole or a pharmaceutically acceptable salt thereof represented by formula (I) and a pharmaceutically acceptable carrier or excipient.

[0014]

[0015] The pharmaceutical composition includes tablets, capsules, granules, pills, pellets, pre-emulsions, microemulsions, suspensions, syrups, enteric-coated preparations, and injections.

[0016] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered in any administration method.

[0017] The dosage of the compound or pharmaceutical composition of the present invention may vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Generally speaking, the suitable dosage range of the compound of the present invention is 26-100 mg / kg body weight per day. The above dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.

[0018] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0019] Beneficial technical effects

[0020] In the present invention, itraconazole gavage significantly improves the motor dysfunction of rotenone-induced PD mouse model. The behavioral results mainly show that compared with the model group, itraconazole was continuously administered for 6 weeks, which can significantly increase the residence time of rotenone mice on the rotating stick, improve the climbing ability of rotenone-induced PD mice, and significantly improve the exercise ability of PD mice on the balance beam. In the A53T PD transgenic mouse model, itraconazole was continuously administered for 8 weeks, which can significantly improve the motor defect of A53T transgenic mice. The behavioral results mainly show that compared with the model group, itraconazole was continuously administered for 8 weeks, which can significantly increase the residence time of A53T transgenic mice on the rotating stick, improve the climbing ability of A53T transgenic PD mice, and significantly improve the exercise ability of A53T transgenic PD mice on the balance beam. In the present invention, itraconazole has the same efficacy as the positive drug levodopa, and itraconazole has been used clinically for antifungal for many years without serious adverse reactions. Based on the above information, itraconazole is safe and effective for PD treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Effect of the test drug itraconazole on the residence time on the rotarod in rotenone-induced PD mice. ### P<0.001vs. control group mice; ***P<0.001vs. model group mice.

[0022] Figure 2 Effects of the test drug itraconazole on the pole climbing scores of rotenone-induced PD mice. ### P<0.001vs. control group mice; ***P<0.001vs. model group mice.

[0023] Figure 3 Effects of the test drug itraconazole on the balance beam test in rotenone PD mice. # P<0.05, ## P<0.01, ### P<0.001vs. control group mice; ***P<0.01, ***P<0.001vs. model group mice.

[0024] Figure 4 Effects of itraconazole administration on rotarod behavior in A53T transgenic mice. ### P<0.001 vs. wild-type mice, *P<0.05, **P<0.01 vs. A53T transgenic mice.

[0025] Figure 5 Effects of itraconazole administration on pole-climbing behavior of A53T transgenic mice. ### P<0.001 vs. wild-type mice, **P<0.01, ***P<0.001 vs. A53T transgenic mice.

[0026] Figure 6 Effects of itraconazole administration on the balance beam behavior of A53T transgenic mice. ### P<0.001 vs. wild-type mice *P<0.05, **P<0.01, ***P<0.001 vs. A53T transgenic mice. DETAILED DESCRIPTION

[0027] The present invention provides the use of itraconazole in preparing a drug for treating and / or preventing PD. The following examples are given to further illustrate the present invention, but the present invention is not limited in any way.

[0028] Example 1 Testing of compounds using rotenone PD animal model

[0029] 1 Establishment of rotenone (Rot)-induced PD mouse model and administration method

[0030] SPF grade C57BL / 6J (male), 8 weeks old, 45, weighing 23-25g, purchased from Beijing Huafukang Biotechnology Co., Ltd. Under room temperature, placed in a barrier-level SPF animal room feeding box for routine feeding, 5 per box, free access to food and water. All operations in the experiment followed the regulations of the Beijing Experimental Animal Ethics Committee. C57 / BL6J mice were adaptively raised in the GLP animal room for three days, and then the mice were randomly divided into a blank control and a model group. The blank control mice were given a solvent, and the model group mice were gavaged with rotenone (30mg / kg), once a day, for 28 consecutive days. On the 14th day of modeling, the model group mice were grouped by rotating rod behavior, divided into rotenone model group (Rot group), itraconazole administration group (26mg / kg). On the 15th day, after giving the modeling agent 2h, gavage began to give the corresponding dose of drugs, once a day, for 28 consecutive days. On the 42nd day of the experiment, the turning rod, climbing pole and balance beam behavior tests were carried out. After the last behavioral test, the animals were processed. The eyeballs of each group of mice were removed to collect blood, which was left to stand at room temperature for 2 hours and centrifuged at 3000 rpm for 10 minutes to obtain serum, which was stored in a -80°C refrigerator for later use. In addition, the brains of 4 mice in each group were fixed in 4% paraformaldehyde, and the striatum and midbrain of the remaining mice were obtained for subsequent research.

[0031] The test drug ITRA was provided by Shanghai MacLean Biochemical Technology Co., Ltd., and rotenone was purchased from Sigma. Preparation: ITRA was prepared into a 2.6 mg / mL uniform solution with 0.5% CMC-Na, and rotenone was prepared into a 3 mg / mL suspension with 0.5% CMC-Na solution. Protect from light and prepare before use.

[0032] 2. Detection indicators

[0033] (1) Rotarod test: The rotarod test is a classic method for evaluating the motor coordination ability of mice. The rotarod instrument (UgoBasie) has a horizontal metal rod (3 cm in diameter) of about 50 cm long, which is divided into 5 sections by metal plates and separated by baffles to prevent the animals from being affected by each other. The rotarod instrument rotates at a constant speed of 25 r / min. The mouse is then placed on the rod and timing is started until the mouse falls off the rod. The latency period (i.e., the time of the first fall) is recorded as the latency period, which indicates its motor coordination ability. Each mouse is tested twice, with an interval of 30 minutes, and the average of the two results is taken.

[0034] (2) Pole climbing test: Pole climbing test is often used to evaluate the limb coordination of mice during movement. Use a 13mm diameter and 150mm high pole climbing instrument (Institute of Materia Medica, Chinese Academy of Medical Sciences), set it vertically, place the mouse head down on the top of the metal pole, let it climb down the pole naturally, and observe the behavior of the animal during the descent. The behavior of the mouse during the descent is scored according to the standard, and the scoring criteria are as follows:

[0035] 5 points: Use all four limbs to crawl down step by step in a coordinated manner;

[0036] 4 points: crawling down step by step but also sliding with hind limbs;

[0037] 3 points: After climbing half the distance, slide down, but hold on to the metal pole;

[0038] 2 points: Sliding behavior occurs before climbing more than half the distance;

[0039] 1 point: After climbing half the distance, the student cannot grab the pole and falls off the pole;

[0040] 0 points: Failed to grab the pole before climbing half the distance and fell off the pole.

[0041] (3) Balance beam test: The balance beam is a square wooden pole 100 cm long and 1 cm wide, with a black box covered with sawdust at one end. The experiment is divided into a training period and a test period. During the training period, the mouse is placed on the balance beam 80 cm away from the end of the black box and allowed to walk into the black box. The test is conducted 30 minutes later. The mouse is placed 80 cm away from one end of the balance beam and allowed to walk to the black box at the other end. The time it takes for the mouse to pass the balance beam from the starting position to the time when all four limbs enter the black box within 60 seconds and the number of times it falls are recorded. At the same time, the behavior of the mouse on the balance beam is recorded and scored according to Feeney's scoring standard. The scoring standard is as follows:

[0042] 0 points means crossing the balance beam without falling;

[0043] 1 point means that the chance of falling while crossing the balance beam is less than 50%;

[0044] 2 points means that the chance of falling while crossing the balance beam is greater than 50%;

[0045] A score of 3 means that the person can cross the balance beam, but the affected hind limb on the paretic side cannot help move forward;

[0046] 4 points means that the person cannot cross the balance beam, but can sit on it;

[0047] A score of 5 means that the mouse will fall off the balance beam if placed on it.

[0048] 3 Statistical analysis

[0049] The experimental data were presented as mean ± standard error (Mean ± SEM). The differences among different groups were compared using one-way analysis of variance (One-Way ANOVA), and P < 0.05 indicated a significant difference.

[0050] 4 Experimental results

[0051] 4.1 Effects of itraconazole on the rotarod test in rotenone-induced PD mice

[0052] The results are shown in Table 1 and Figure 1 . Movement disorder is the main pathological feature of PD. In order to detect whether the rotenone-induced model mice have PD-like movement symptoms, the mouse rotating stick test was performed at the end of the sixth week of the experiment. The rotating stick test is a common experimental method for detecting the motor coordination ability of rodents. The results of the rotating stick test showed that the time that the mice in the rotenone model group stayed on the rotating stick was significantly lower than that in the blank control group, and the administration of itraconazole can significantly increase the time that the mice stayed on the rotating stick. The results showed that the test drug itraconazole had a good improvement effect on the motor coordination dysfunction of rotenone PD mice after administration.

[0053] Table 1 Effects of itraconazole on the rotarod test in rotenone PD mice (n=11-15)

[0054]

[0055] ### P < 0.001, compared with the blank control group; *** P<0.001, compared with the model group.

[0056] 4.2 Effects of itraconazole on the pole climbing test of rotenone-induced PD mice

[0057] The results are shown in Table 2 and Figure 2 . The pole climbing test can be used to determine the motor function of the mouse's limbs. The mouse climbing test was performed at the end of the sixth week of the experiment. The results showed that the climbing test scores of the mice in the rotenone model group were significantly lower than those in the blank control group, and itraconazole could significantly improve the climbing test scores of the mice. The results showed that itraconazole had a good improvement effect on the motor dysfunction of rotenone PD mice.

[0058] Table 2 Effect of itraconazole on the pole climbing test of rotenone PD mice (n=11-15)

[0059]

[0060] ### P < 0.001, compared with the blank control group; *** P<0.001, compared with the model group.

[0061] 4.3 Effects of itraconazole on the balance beam test in rotenone-induced PD mice

[0062] The results are shown in Table 3 and Figure 3 . The balance beam test is usually used to evaluate the fine motor ability, balance and coordination of the forelimbs and hindlimbs of mice. The evaluation indicators include the time it takes for the mouse to cross the wooden pole during the forward movement, the number of errors of the limbs slipping, and the score. The balance beam test was performed at the end of the sixth week of the experiment. The results showed that the time, number of falls, and scores of the rotenone model group mice on the balance beam were significantly higher than those of the blank control group mice. The administration of itraconazole can significantly reduce the time, number of falls, and scores of the mice on the balance beam. The above results show that itraconazole can significantly improve the motor dysfunction of PD mice.

[0063] Table 3 Effects of itraconazole on the balance beam test of rotenone PD mice (n=11-15)

[0064]

[0065] ### P < 0.001, compared with the blank control group; * P<0.05, *** P<0.001, compared with the model group.

[0066] Example 2 Compound detection using A53T transgenic PD mouse model

[0067] Establishment of 1A53T transgenic PD mice and drug administration method

[0068] SPF grade α-Syn (A53T) (male), 6 months old, 60 mice, weighing 22-24g, SPF grade wild-type C57BL / 6J mice (WT mice, male), 6 months old, 22 mice, weighing 22-24g, were purchased from Changzhou Cavens Laboratory Animal Co., Ltd. They were placed in barrier-grade SPF animal room breeding boxes at room temperature, 5 mice per box, and had free access to food and water. All operations in the experiment followed the regulations of the Beijing Experimental Animal Ethics Committee.

[0069] α-Syn(A53T) and WT mice at 6 months old were tested for behavior once a month. At 12 months old, A53T transgenic mice showed behavioral disorders. According to the behavioral results, A53T mice were divided into A53T model group, itraconazole group (26 mg / kg), and positive control levodopa group (20 mg / kg), with 13-20 mice in each group. Mice in each treatment group were given corresponding doses of drugs by gavage at 10 mL / kg for 8 consecutive weeks, and mice in the WT group and A53T group were given corresponding doses of solvent by gavage. Behavioral tests of turning sticks, climbing poles, and balance beams were performed in the second month after administration. After the last behavioral test, the animals were processed, the eyeballs of mice in each group were removed to collect blood, and the blood was left at room temperature for 2 hours, centrifuged at 3000 rpm for 10 minutes, and the serum was placed in a -80℃ refrigerator for storage. In addition, the brains of 4 mice in each group were fixed in 4% paraformaldehyde, and the striatum and midbrain of the remaining mice were taken for subsequent studies.

[0070] The test drug ITRA was provided by Shanghai MacLean Biochemical Technology Co., Ltd., and the positive control drug levodopa tablets were provided by Beijing Shuguang Pharmaceutical Co., Ltd.; levodopa was prepared into a 2 mg / ml solution with 0.5% CMC-Na, and itraconazole was prepared into a 2.6 mg / mL uniform solution with 0.5% CMC-Na.

[0071] 2. Detection indicators:

[0072] (1) Rotarod test: The horizontal metal rod (3 cm in diameter) of the rotarod instrument (Ugo Basie) is about 50 cm long and divided into 5 sections by metal plates. The animals are separated by baffles to prevent each other from being affected. The rotarod instrument rotates at a constant speed, and then the mouse is placed on the rod. The timing is started until the mouse falls off the rod. The latency (i.e., the time of the first fall) is recorded to indicate its motor coordination ability. Each mouse is tested twice, with an interval of 30 minutes, and the average of the two results is taken.

[0073] (2) Pole climbing test: A 13 mm diameter, 150 mm high pole climbing apparatus (Institute of Materia Medica, Chinese Academy of Medical Sciences) was erected vertically. The mouse was placed head down on the top of the metal pole and allowed to naturally climb down the pole. The behavior of the animal during the descent was observed. The behavior of the mouse during the descent was scored according to the standard. The scoring criteria are as follows: 5 points: using all four limbs to crawl down step by step in a coordinated manner;

[0074] 4 points: crawling down step by step but also sliding with hind limbs;

[0075] 3 points: After climbing half the distance, slide down, but hold on to the metal pole;

[0076] 2 points: Sliding behavior occurs before climbing more than half the distance;

[0077] 1 point: After climbing half the distance, the student cannot grab the pole and falls off the pole;

[0078] 0 points: Failed to grab the pole before climbing half the distance and fell off the pole. 5 Insulin resistance index detection (3) Balance beam test: The balance beam is a square wooden pole 100 cm long and 1 cm wide, with a black box covered with sawdust at one end. The experiment is divided into a training period and a test period. During the training period, the mouse is placed on the balance beam 80 cm away from the end of the black box and allowed to walk into the black box. The test is carried out 30 minutes later. The mouse is placed 80 cm away from one end of the balance beam and allowed to walk to the black box at the other end. The time it takes for the mouse to pass the balance beam from the starting position to the time when all four limbs enter the black box within 60 seconds and the number of times it falls are recorded. At the same time, the behavior of the mouse on the balance beam is recorded and scored according to Feeney's scoring standard. The scoring standard is as follows:

[0079] 0 points means crossing the balance beam without falling;

[0080] 1 point means that the chance of falling while crossing the balance beam is less than 50%;

[0081] 2 points means that the chance of falling while crossing the balance beam is greater than 50%;

[0082] A score of 3 means that the person can cross the balance beam, but the affected hind limb on the paretic side cannot help move forward;

[0083] 4 points means that the person cannot cross the balance beam, but can sit on it;

[0084] A score of 5 means that the mouse will fall off the balance beam if placed on it.

[0085] 3 Statistical analysis

[0086] The experimental data were presented as mean ± standard error (Mean ± SEM). The differences among different groups were compared using one-way analysis of variance (One-Way ANOVA), and P < 0.05 indicated a significant difference.

[0087] 4 Experimental results

[0088] 4.1 Effects of itraconazole on the rotarod behavior of A53T transgenic mice

[0089] The results are shown in Table 4 and Figure 4 Movement disorder is the main pathological feature of PD. In order to detect whether A53T transgenic mice have PD-like movement symptoms, each group of mice was subjected to a rotating stick test at the end of the 8th week of drug administration. The rotating stick test is a common experimental method for detecting the motor coordination ability of rodents. The results of the rotating stick test showed that the time that mice in the itraconazole and levodopa groups stayed on the rotating stick was significantly increased compared with that of mice in the A53T group, indicating that the test drug itraconazole had a good improvement effect on the motor coordination dysfunction of A53T mice after administration.

[0090] Table 4 Effect of itraconazole on the rotarod test of A53T transgenic mice (n=15-23)

[0091]

[0092] ### P < 0.001, compared with the wild-type group; * P<0.05, ** P<0.01, compared with A53T transgenic group.

[0093] 4.2 Effects of itraconazole on pole-climbing behavior of A53T transgenic mice

[0094] The results are shown in Table 5 and Figure 5 The pole climbing test can be used to determine the motor function of the mouse's limbs. Each group of mice was subjected to a pole climbing test at the end of the 8th week of drug administration. The results of the pole climbing test showed that the scores of the itraconazole and levodopa groups were significantly different from those of the A53T mice, indicating that itraconazole had a certain improvement effect on the motor dysfunction of A53T mice.

[0095] Table 5 Effect of itraconazole on the pole climbing test of A53T transgenic mice (n=15-23)

[0096]

[0097] ### P < 0.001, compared with the wild-type group; ** P<0.01, *** P<0.001, compared with A53T transgenic group.

[0098] 4.3 Effects of itraconazole on the balance beam behavior of A53T transgenic mice

[0099] The results are shown in Table 6 and Figure 6 . The balance beam experiment is usually used to evaluate the fine motor ability, balance and coordination of the forelimbs and hindlimbs of mice. The evaluation indicators include the time taken by the mouse to cross the wooden pole during the forward movement, the number of errors and scores of the limbs slipping. Each group of mice underwent a balance beam test at the end of the 8th week of drug administration. The results showed that the time spent on the balance beam, the number of falls and the score of the A53T transgenic mice were significantly higher than those of the blank control group mice. The number of errors and behavioral scores of the mice in the itraconazole group were significantly reduced. The time spent crossing the balance beam, the number of slips and the behavioral scores of the mice in the levodopa group were significantly reduced. The above results indicate that itraconazole can significantly improve the motor dysfunction of PD mice.

[0100] Table 6 Effect of itraconazole on the pole climbing test of A53T transgenic mice (n=15-23)

[0101]

[0102] ### P<0.001, compared with the wild-type group; #P<0.05, ## P<0.01, ### P<0.001, compared with A53T transgenic group.

Claims

1. Use of itraconazole or a pharmaceutically acceptable salt thereof as represented by formula (I) in the preparation of a drug for treating and / or preventing Parkinson's disease, 2. Use of a pharmaceutical composition in the preparation of a drug for treating and / or preventing Parkinson's disease, characterized in that: The pharmaceutical composition comprises itraconazole represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

3. The use according to claim 3, characterized in that The pharmaceutical composition includes tablets, capsules, granules, pills, dripping pills, pre-emulsions, microemulsions, suspensions, syrups, enteric-coated preparations, and injections.

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