Application of N-acyl dopamine family lipid in prevention and treatment of drug-induced motor complications of Parkinson's disease

Abstract

The invention provides an application of N-acyl dopamine family lipids in prevention and treatment of drug-induced motor complications of Parkinson's disease, and belongs to the field of biological medicine. The invention provides the application of the NADs compound as the levodopa partner medicine for preventing or treating levodopa-induced dyskinesia for the first time. According to the invention, an LID animal model is subjected to 6-hydroxydopamine midbrain nigra positioning injection and levodopa intraperitoneal injection molding as research objects, and the effect of NADs in improving LID is researched. The result shows that the NADs can significantly improve the drug-induced PD motor complication LID, indicating that the NADs compound can be used as a partner drug to assist levodopa in treating PD.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to the application of N-acyl dopamine family lipids in preventing or treating drug-induced motor complications of Parkinson's disease. Background Art

[0002] Parkinson's disease (PD), also known as Parkinson's paralysis, is a chronic neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra compacta of the midbrain and the appearance of Lewy bodies in neurons. Epidemiological data show that the prevalence rate in people over 60 years old is 2%, which is a heavy burden that needs to be urgently addressed in the aging society. For half a century, dopamine replacement therapy based on levodopa has been regarded as the gold standard for the treatment of Parkinson's disease. Levodopa can cross the blood-brain barrier and be metabolized into dopamine in the body, thereby replenishing this neurotransmitter. However, this treatment regimen is not a cure for the disease and can only temporarily relieve the patient's behavioral symptoms, but cannot prevent the continued loss and death of neurons. After 3-5 years of treatment, most patients will experience a series of motor complications such as levodopa-induced dyskinesia. These complications seriously affect the quality of life of patients and become one of the main causes of disability in patients with Parkinson's disease. The motor complications caused by levodopa mainly include motor fluctuations and levodopa-induced dyskinesia (LID). According to clinical manifestations, motor fluctuations can be divided into four types: end-of-dose phenomenon, on-time delay, on-off phenomenon and freezing of gait, while dyskinesia includes three types: peak-dose dyskinesia, off-time dystonia and biphasic dyskinesia. Since levodopa has a short half-life and rapid absorption and metabolism, fluctuations in its blood concentration will affect signaling pathways such as dopamine D1 / D2 receptors, glutamate receptors and serotonin receptors, triggering a series of complex cascade reactions involving neurons and non-neuronal cells, so its pathological mechanism is still not fully understood.

[0003] In terms of treatment, in addition to surgical methods such as deep brain stimulation and unilateral pallidotomy, the currently available drug options are very limited, mainly including amantadine, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors. However, the efficacy of these drugs is often difficult to sustain and may cause new side effects. To date, there is still a lack of effective treatment for drug-induced movement complications, which has led to a dilemma for patients in the use of anti-Parkinson's drugs.

[0004] N-acyldopaminelipids (NADs) are a class of endogenous cannabinoid family compounds. Currently known family members include N-arachidonoyl dopamine (NADA), N-oleoyl dopamine (OLDA), N-docosahexaenoyl dopamine (NDHA), N-palmitoyl dopamine (PALDA), N-stearoyl dopamine (STERDA) and N-octanoyl dopamine (NOD). As members of the cannabinoid family, they can activate transient receptor potential cation channels (TRPV1) and play an important role in nociception, or activate cannabinoid receptors CB1 and CB2 to support neural activity. At present, the structural characteristics and physiological activities of NADs have not been well characterized. It is of great significance to develop a complete class of NADs and characterize their physiological activities. Summary of the invention

[0005] In order to solve the problem of insufficient drugs in the prior art for preventing or treating drug-induced motor complications of Parkinson's disease, the present invention proposes an application of NADs compounds in the field of preventing and treating drug-induced motor complications of Parkinson's disease. The present invention particularly points out that NADs compounds can be used as an adjuvant drug of levodopa to prevent or treat drug-induced motor complications of Parkinson's disease.

[0006] Specifically, the present invention is realized through the following technical solutions:

[0007] In the first aspect of the present invention, a NADs compound (as shown in Formula I) or a pharmaceutically acceptable acid addition salt thereof is provided:

[0008]

[0009] Wherein, R1 is selected from C 6～26 Straight chain saturated hydrocarbons, C 6～26 Branched chain saturated hydrocarbons, C 6～26 Straight chain unsaturated hydrocarbons, C 6～26 Branched unsaturated hydrocarbons, C 3～24 Cyclic hydrocarbons, C 6～24 Aromatic hydrocarbon; R2 is monosubstituted or polysubstituted, and the substituents are selected from hydrogen, halogen, nitro, hydroxyl, C 1～4 Alkyl, C 1～4 Alkyl halides, C 1～4 Alkoxy, C 1～4 Haloalkoxy; n is 1, 2 or 3, and its basic unit contains at least one carbon-carbon single bond or one carbon-carbon double bond; X is O or S.

[0010] Preferably, the R1 is selected from C 12～26 Straight chain saturated hydrocarbons, C 12～26 Branched chain saturated hydrocarbons, C 12～26Straight chain unsaturated hydrocarbons, C 12～26 Branched unsaturated hydrocarbons, C 3～24 Cyclic hydrocarbons, C 6～24 Aromatic hydrocarbon. R2 is selected from one or more of hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, thiotrifluoromethyl, or trifluoroethyl. n is 1 or 2, and its basic unit contains at least one carbon-carbon single bond or one carbon-carbon double bond; X is O.

[0011] More preferably, said R1 is selected from C 12～26 Straight chain unsaturated hydrocarbons, C 12～26 Branched unsaturated hydrocarbon; R2 group is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 3,4-dihydroxy, 2,6-dihydroxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 4-bromo, 2,6-dichloro; n is 1, and its basic unit is a carbon-carbon single bond; X is O.

[0012] Specifically, the R1 is selected from C 12～26 Straight chain unsaturated hydrocarbons, the corresponding carboxylic acid compounds are

[0013] 2,5,8,11,14,17,20,23-octaoxacosan-26-oic acid, 2,5,8,11-tetraoxatetradecane-14-oic acid, cis-5,8,11,14,17-eicosapentaenoic acid, 5,8,11-trioxa-2-azatridecanedioic acid-1-tert-butyl ester, 15-bromopentadecanoic acid, (6Z,9Z,12Z)-octadecyl-6,9,12-trienoic acid, heptadecanoic acid, (9Z,12Z)-octadecyl-9,12-dienoic acid, (9Z)-9-octadecenoic acid, (5Z,8Z,11Z,1 4Z)-5,8,11,14-eicosatetraenoic acid, cis-9-hexadecenoic acid, (10E,12Z)-octadecyl-10,12-dienoic acid, (9Z,12Z,15Z)-9,12,15-octadecatrienoic acid; R2 group is hydrogen, 3,4-dihydroxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 4-fluoro, 4-bromo, 4-hydroxy, 4-methyl, 3,4-dimethoxy, 3-hydroxy-4-methoxy, 2,6-dichloro; n is 1, and its basic unit is a carbon-carbon single bond; X is O.

[0014] Furthermore, the NADs compound may also be a pharmaceutically acceptable salt or solvate thereof.

[0015] The NADs compound of the present invention can be prepared in various dosage forms according to conventional production methods in the pharmaceutical field, such as mixing the active ingredient with one or more carriers and then preparing it into a desired dosage form. For example, the NADs compound itself or a mixture thereof with a pharmaceutically acceptable excipient, diluent, etc. can be prepared into a pharmaceutical composition in the form of tablets, pills, oral liquids, capsules, syrups, drop pills, granules, injections, powder injections, sprays, aerosols, powder sprays or suppositories.

[0016] In addition, taking X as O and n=1 as an example, the preparation process of the NADs compound is as follows:

[0017]

[0018] Further, in the presence of a diluent, the compound Mix with the condensing agent and slowly add the compound solution Finally, a base is added and the reaction is carried out at room temperature for 1 to 4 hours to obtain the target product.

[0019] Further, the condensing agent is one of N,N'-carbonyldiimidazole, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyl uronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, preferably N,N'-carbonyldiimidazole.

[0020] Furthermore, the diluent is an inert organic solvent, in particular an aliphatic, alicyclic or aromatic optionally halogenated hydrocarbon, specifically selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether and diethylene glycol monoethyl ether; preferably at least one of N,N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.

[0021] Further, the presence of a base is conducive to the reaction, and the base is preferably sodium hydroxide, potassium carbonate, sodium ethoxide, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane, diazabicyclononene or diazabicycloundecene. Preferably, the base is triethylamine.

[0022] The present invention provides a use of the NADs compound in preventing or treating drug-induced motor complications of Parkinson's disease.

[0023] As an alternative, in the above use, the motor complications of Parkinson's disease are levodopa-induced, that is, the drug is levodopa.

[0024] As an optional mode, in the above use, the Parkinson's disease motor complications include movement fluctuations and dyskinesias.

[0025] As an optional mode, in the above-mentioned use, the movement complications include abnormal involuntary movements of the axial, limb and orofacial regions, wherein the abnormal involuntary movements of the axial region are twisting movements of the neck and upper body toward the contralateral side of the injury, the abnormal involuntary movements of the limbs are repetitive jumping or dystonia postures of the contralateral forelimbs, and the abnormal involuntary movements of the orofacial region are jaw movements and contralateral tongue protrusion.

[0026] As an alternative, in the above use, the NADs compound is used as a chaperone drug of levodopa for preventing or treating levodopa-induced dyskinesia (LID).

[0027] The present invention uses LID behavioral data as the main indicator for evaluating the improvement effect of LID, detects and calculates the score of abnormal involuntary movement (AIM), so as to prove that NADs has a significant improvement effect on LID.

[0028] The AIM score includes the assessment of the axial, limb and oral-facial parts. The observation method is: after the administration of levodopa, a 1-minute observation is performed every 30 minutes, and the whole process lasts for 120 minutes.

[0029] The pathogenic mechanism of LID is diverse. The present invention uses 6-hydroxydopamine (6-OHDA) to simulate the damage of nerve cells caused by neurotoxicity to cause PD, and uses levodopa to induce LID symptoms in animal models.

[0030] As an alternative, in the above use, the dosage of the NADs compound for preventing or treating drug-induced motor complications of Parkinson's disease is 1-10 mg / kg.

[0031] Preferably, the dosage of the NADs compound for preventing or treating drug-induced motor complications of Parkinson's disease is 5 mg / kg.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention proposes for the first time that NADs compounds can be used as levodopa partner drugs to prevent or treat levodopa-induced dyskinesia. The present invention uses the LID animal model of 6-hydroxydopamine midbrain substantia nigra localized injection and levodopa intraperitoneal injection modeling as research objects to study the role of NADs in improving LID. The results show that the NADs of the present invention can significantly improve drug-induced PD motor complications LID, indicating that NADs compounds can be used as partner drugs to assist levodopa in treating PD. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0035] Figure 1 Show the LID modeling and grouping medication process;

[0036] Figure 2 The results showed that the modeling and drug administration methods had no significant effect on the body weight of mice;

[0037] Figure 3 Shows the effects of each group of drugs on the axial scores of abnormal involuntary movements of mice;

[0038] Figure 4 Show the effects of each group of drugs on the limb direction scores of abnormal involuntary movements of mice;

[0039] Figure 5 Shown are the effects of each group of drugs on the oral-facial scores of abnormal involuntary movements of mice;

[0040] Figure 6 The results show the effects of each group of drugs on the total score of abnormal involuntary movements of mice. DETAILED DESCRIPTION

[0041] The present invention provides the use of NADs to improve PD motor complications. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications of this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0042] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0043] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0044] The present invention will be further described below in conjunction with embodiments:

[0045] Example 1

[0046] 1. Experimental Materials and Instruments

[0047] 1. Experimental Animals

[0048] C57BL / 6J mice, male, 6 weeks old, weighing 20-22 g, were purchased from the Experimental Animal Management Center of Southern Medical University (License: SCXK (Guangdong) 2021-0041). The animals were raised in the Medical Experimental Animal Center of Jinan University at a temperature of 23±2°C, a humidity of 50±10%, and standard mouse feed. The experimental animals in each group were allowed to eat and drink freely.

[0049] 2. Main experimental reagents

[0050] 6-OHDA (Sigma, H4381), L-dopa (Sigma, D9628), Benserazide (Sigma, B7283), Apomorphine (Sigma, A4393), Dopamine hydrochloride (Annaiji Chemical, E0801830250), Arachidonic acid (Annaiji, A875622), Docosahexaenoic acid (Annaiji, BD121651), Oleic acid (Annaiji, O815203). N-Arachidonic acid dopamine (Cayman, 90057), N-Oleoyl dopamine (Cayman, 10115), N-Docosahexaenoyl dopamine (Cayman, 9001394).

[0051] 3. Main experimental instruments

[0052] Mouse stereotaxic instrument (Shenzhen Ruiwode Life Science Co., Ltd.), mouse rotarod instrument (UgoBasile, Italy).

[0053] 2. Experimental Methods and Results

[0054] 1. LID Model Preparation

[0055] First, 6-OHDA was used to construct a PD model: After seven days of adaptive feeding, the mice were weighed and deeply anesthetized with isoflurane gas. The head hair was shaved with a razor and the mice were fixed in a brain stereotaxic instrument. The left and right ear bars were adjusted to make the fixation more stable. The skin of the mouse head was cut along the midline to expose the mouse skull, and hydrogen peroxide was used to wipe to fully expose the bregma and lambda. With the bregma as the coordinate origin, referring to the "Mouse Brain Stereotaxic Atlas", the injection coordinate site was AP: +0.3, L: +2.3, DV: -2.9, and a small hole was carefully drilled with a skull drill (to avoid damaging brain tissue). 1.5 μL of 5 μg / μL 6-OHDA was slowly injected at a speed of 0.1 μL / min. After the injection, the needle was retained for 5 minutes, and the needle was slowly returned. The scalp was sutured to complete the brain localization injection. 21 days after the injection, apomorphine (0.5 mg / kg) was injected intraperitoneally to induce the mice to rotate to the healthy side. The test was performed three times, each time for 10 minutes, and the average value was taken. Those with more than 70 rotations were selected as successful models, and the other mice were eliminated.

[0056] Secondly, after the mouse PD model was successfully established, levodopa was used. During administration, levodopa and benserazide were mixed in a ratio of 4:1 to construct the LID model. The above PD model mice were intraperitoneally injected with levodopa (20 mg / kg) every day, and 6-OHDA was used to verify the success of the PD model as Day 0, which lasted for a total of 42 days. The experimental process is as follows Figure 1 shown.

[0057] 2. Experimental Grouping and Weight Monitoring

[0058] The experimental mice were divided into 6 groups: 6 mice without treatment were set as blank group (Sham). The mice with successful PD model were randomly divided into 5 groups, 6 mice in each group, namely: 6-OHDA group, 6-OHDA+levodopa group, 6-OHDA+levodopa+NADA (5 mg / kg, tail vein injection) group, 6-OHDA+levodopa+NDHA (5 mg / kg, tail vein injection) group and 6-OHDA+levodopa+OLDA (5 mg / kg, tail vein injection) group.

[0059] Weight monitoring: Figure 2 As shown, the body weight data for 6 consecutive weeks showed that the modeling and drug administration methods used in this experiment had no significant effect on the body weight of mice.

[0060] 3. Behavioral methods and results: Abnormal involuntary movement score (AIM)

[0061] Method description: The AIM score is divided into three parts, including axial, limb and orofacial. Each observation was conducted every 30 minutes after the administration of levodopa, and each observation lasted for 1 minute for a total of 120 minutes. (1) Axial AIM: twisting movement of the neck and upper body toward the opposite side of the injury; (2) Limb AIM: repetitive jumping or dystonic posture of the contralateral forelimb; (3) Orofacial AIM: open jaw movement and contralateral tongue protrusion. Each subtype was scored from 1 to 4 according to the intensity of the movement disorder during the observation period, 0: no movement disorder; 1: occasional occurrence (less than 30 seconds); 2: frequent occurrence (more than 30 seconds); 3: symptoms persisted and stopped after external stimulation; 4: persisted and did not stop after stimulation. The total AIM score is the accumulation of the scores of each part in each observation period.

[0062] Experimental results: According to the abnormal AIM principle, the effects of NADA, NDHA, and OLDA on LID induced by levodopa were evaluated. Figure 3-Figure 6 As shown, including axial AIM score ( Figure 3 ), oral-facial AIM score ( Figure 4 ), limb-directed AIM score ( Figure 5 ) and AIM total score ( Figure 6 ). Compared with the 6-OHDA group alone, the AIM scores of mice in the levodopa group increased significantly on the 7th, 21st and 42nd days. The longer the administration time, the higher the AIM score, indicating that long-term administration of levodopa induced LID behavioral disorders in the PD model. There was no significant difference in the improvement of the AIM scores on the 7th day by NADA, NDHA and OLDA treatment, but the AIM scores of mice on the 21st and 42nd days were significantly alleviated ( * p<0.05,

[0063] ** p<0.01, *** p<0.001vs.6-OHDA group, # p<0.05, ## p<0.005, ### p<0.001 vs. 6-OHDA+levodopa group. N=6 mice in each group). The above data prove that NADs treatment can improve LID induced by levodopa.

[0064] The above description of the embodiments is to facilitate the understanding and application of the present invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the embodiments herein, and improvements and modifications made to the present invention by those skilled in the art based on the disclosure of the present invention should be within the scope of protection of the present invention.

Claims

1. Use of an N-acyl dopamine family lipid in the preparation of a drug for preventing and treating drug-induced motor complications of Parkinson's disease, wherein the N-acyl dopamine family lipid has a structure as shown in Formula I or a pharmaceutically acceptable pharmaceutical acid addition salt thereof: in, R1 is selected from C 6～26 Straight chain saturated hydrocarbons, C 6～26 Branched chain saturated hydrocarbons, C 6～26 Straight chain unsaturated hydrocarbons, C 6～26 Branched unsaturated hydrocarbons, C 3～24 Cyclic hydrocarbons, C 6～24 Aromatic hydrocarbons; R2 is monosubstituted or polysubstituted, and the substituents are selected from hydrogen, halogen, nitro, hydroxyl, C 1～4 Alkyl, C 1～4 Alkyl halides, C 1～4 Alkoxy, C 1～4 Haloalkoxy; n is 1, 2 or 3, and its basic unit contains at least one carbon-carbon single bond or one carbon-carbon double bond; X is O or S.

2. The use according to claim 1, characterized in that The R1 is selected from C 12～26 Straight chain saturated hydrocarbons, C 12～26 Branched chain saturated hydrocarbons, C 12～26 Straight chain unsaturated hydrocarbons, C 12～26 Branched unsaturated hydrocarbons, C 3～24 Cyclic hydrocarbons, C 6～24 Aromatic hydrocarbons; R2 is selected from one or more of hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, thiotrifluoromethyl, or trifluoroethyl; n is 1 or 2, and its basic unit contains at least one carbon-carbon single bond or one carbon-carbon double bond; X is O.

3. The use according to claim 2, characterized in that The R1 is selected from C 12～26 Straight chain unsaturated hydrocarbons, C 12～26 Branched unsaturated hydrocarbons; R2 is selected from hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 3,4-dihydroxy, 2,6-dihydroxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 4-bromo, 2,6-dichloro; n is 1, and its basic unit is a carbon-carbon single bond; X is O.

4. The use according to claim 3, characterized in that The R1 is selected from C 12～26 Straight chain unsaturated hydrocarbons, C 12～26 Branched unsaturated hydrocarbons; R2 is selected from hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 3,4-dihydroxy, 2,6-dihydroxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 4-bromo, 2,6-dichloro; n is 1, and its basic unit is a carbon-carbon single bond; X is O.

5. The use according to claim 1, characterized in that The N-acyl dopamine family lipids are selected from NADA, NDHA and OLDA.

6. The use according to claim 1, characterized in that The drug that induces motor complications in Parkinson's disease is levodopa.

7. A drug for preventing and treating drug-induced motor complications of Parkinson's disease, characterized in that: Comprising N-acyl dopamine family lipids, preferably, the N-acyl dopamine family lipids are selected from NADA, NDHA and OLDA, and the dosage of the N-acyl dopamine family lipids is 1-10 mg / kg, preferably 5 mg / kg; The drug that induces motor complications in Parkinson's disease is levodopa.

8. A pharmaceutical composition, characterized in that The invention comprises levodopa and N-acyl dopamine family lipids, preferably, the N-acyl dopamine family lipids are selected from NADA, NDHA and OLDA, and the dosage of the N-acyl dopamine family lipids is 1-10 mg / kg, preferably 5 mg / kg.

9. The drug according to claim 7, characterized in that It also includes pharmaceutically acceptable excipients and / or diluents, and the dosage form of the drug is one of pills, oral liquids, capsules, granules, injections, powder injections, sprays, or suppositories.

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