Application of chlorogenic acid in preparation of medicine for preventing or treating autoimmune demyelination disease

Abstract

The invention belongs to the technical field of medicines, and discloses application of chlorogenic acid as shown in a formula (I) and pharmacodynamically acceptable salts thereof in preparation of medicines for preventing, relieving and / or treating autoimmune demyelination diseases. In a mouse experimental autoimmune encephalomyelitis model, chlorogenic acid shows a good treatment effect, and can effectively prevent and treat pathological changes and disease progression of diseases and relieve the severity of the diseases, thereby providing a new drug and a new structure for clinical treatment.

Description

Technical Field

[0001] This invention relates to the use of chlorogenic acid and / or its pharmaceutically acceptable salts in the preparation of medicaments for the prevention, relief and / or treatment of autoimmune demyelinating diseases, and belongs to the field of pharmaceutical technology. Background Technology

[0002] Multiple sclerosis (MS) is an immune-mediated, chronic, progressive inflammatory demyelinating disease of the central nervous system (CNS). It affects more than 2 million people worldwide, posing a serious threat to human health and imposing a heavy economic burden on society. The pathogenesis of MS is complex, the cause is unknown, and there is currently no cure; patients require long-term treatment. MS is characterized by inflammation and demyelinating lesions in the brain, spinal cord, and optic nerve. Its clinical manifestations are widespread, including muscle weakness, sensory disturbances, cognitive impairment, and fatigue. The etiology of MS is unclear, but it may be related to multiple factors such as genetics, environment, and infection. Based on the patient's clinical presentation, MS can be classified into four types: relapsing-remitting (relapsing and remittent), characterized by alternating periods of relapse and remission with no significant disease progression; primary progressive (primarily progressive), characterized by continuous deterioration after onset; secondary progressive (initially relapsing and remittent), characterized by a relapsing-remitting pattern followed by continuous deterioration; and progressive-relapsing (gradually progressing with relapses). Currently, most clinical treatments target patients with relapsed or remission-type illnesses.

[0003] Multiple sclerosis is considered an autoimmune disease, primarily caused by autoreactive immune cells crossing the blood-brain barrier into the central nervous system (CNS). Early lesions manifest as peripheral immune cell infiltration and blood-brain barrier (BBB) ​​leakage. Cellular infiltration is predominantly dominated by macrophages and CD8+ cells. + T cells followed by CD4 + The number of T cells, B cells, and plasma cells is relatively low. The composition of T cells does not change with disease progression, but the relative proportion of B cells and plasma cells increases. Microglia and macrophages remain chronically activated throughout the disease process, forming plaques of myelin and oligodendrocyte loss. As the disease progresses, focal white matter lesions appear in the brain. Brain and spinal cord damage is not obvious, but brain atrophy is widespread, accompanied by ventricular enlargement. Astrocytes form multiple sclerotic glial scars in the white matter lesions. Demyelination also occurs in the gray matter of the cerebral cortex, nuclei, and spinal cord, but the demyelinated areas of white matter can be partially repaired through myelin regeneration. In addition, the disease process not only affects myelin but also leads to degenerative changes in axons and neurons, resulting in irreversible disability in patients.

[0004] Over the past two decades, as our understanding of the pathogenesis of multiple sclerosis (MS) has deepened, researchers have developed a variety of drugs targeting the disease's unique physiological pathways. Currently, drugs used to treat MS are mainly divided into five categories: immunomodulators, hormones, monoclonal antibodies, interferons, and neurorepair agents. These drugs can alleviate disease progression and control patient symptoms, but they are ineffective in repairing damaged neurons, do not improve functional disabilities, and have serious toxic side effects with long-term use.

[0005] Experimentally allergic encephalomyelitis (EAE) is a classic animal model of multiple sclerosis. It involves the specific activation of brain helper T cells by myelin autoantigens, leading to inflammatory infiltration and demyelination of the central nervous system. Its biochemical, immunological, and pathological characteristics are very similar to those of multiple sclerosis. Furthermore, rat and mouse EAEs can be used to study experimentally allergic encephalomyelitis, neuroencephalomyelitis optica, and acute disseminated encephalomyelitis.

[0006] Myelitis is an ideal animal model for autoimmune demyelinating diseases, as it is similar to human demyelinating diseases in terms of clinical, pathological, immunological, and biochemical changes, and therefore has a wide range of applications.

[0007] The chlorogenic acid described in this invention has the molecular formula C0. 16 H 18 O9, also known as caffeic acid tannin, is chemically named 3-O-caffeoylquinic acid. To date, Chinese patent CN 118593465A (publication number) describes the use of chlorogenic acid in the preparation of drugs for treating diffuse midline gliomas. In this patent, chlorogenic acid is shown to have inhibitory effects on diffuse brainstem gliomas and can inhibit their growth. However, there are no reports, either domestically or internationally, of chlorogenic acid playing a direct or indirect role in autoimmune demyelinating diseases. Therefore, this invention mainly relates to the preparation of drugs and drug combinations using chlorogenic acid, for clinical application in the preparation of drugs for the prevention, relief, and / or treatment of autoimmune demyelinating diseases. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide the use of chlorogenic acid in the preparation of drugs for the prevention, relief and / or treatment of autoimmune demyelinating diseases.

[0009] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0010] The first aspect of the present invention is to provide the use of chlorogenic acid as shown in formula (I) and its pharmacodynamically acceptable salts in the preparation of drugs for the prevention, relief and / or treatment of autoimmune demyelinating diseases.

[0011]

[0012] The autoimmune demyelinating diseases mentioned include, but are not limited to, demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis, leukoencephalitis, and transverse myelitis; and demyelinating autoimmune diseases affecting the peripheral nervous system such as acute inflammatory demyelinating polyneuropathy (AIDP; Guillain-Barré syndrome), chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, motor and sensory neuropathy (HMSN), hereditary sensorimotor neuropathy (HSMN), and peroneal muscular atrophy. Atrophy, progressive neurogenic peroneal muscular atrophy (Charcot-Marie-Tooth Disease), etc.

[0013] The multiple sclerosis includes relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and progressive-relapsing multiple sclerosis.

[0014] An EAE model was established using female C57BL / 6J mice. The effects of chlorogenic acid on animal body weight and disease scores were investigated. Limb strength and treatment outcomes were observed through suspension grading and suspension time experiments. H&E staining and LFB staining were used to detect the ameliorative effect of chlorogenic acid on inflammatory cell infiltration and demyelination in the spinal cord of the experimental animals. Based on these findings, the role of chlorogenic acid in the preparation of drugs for the prevention, alleviation, and / or treatment of autoimmune demyelinating diseases was determined.

[0015] The second aspect of the present invention is to provide the use of a pharmaceutical composition in the preparation of a drug for the prevention, relief and / or treatment of autoimmune demyelinating diseases, characterized in that the pharmaceutical composition contains an effective dose of chlorogenic acid as shown in formula (I), and a pharmaceutical excipient.

[0016]

[0017] The pharmaceutical composition contains chlorogenic acid as the active pharmaceutical ingredient, as well as other active ingredients. The pharmaceutical composition includes the following dosage forms: solution, suspension, lyophilized powder for injection, emulsion, pills, capsules, powder, controlled release, sustained release formulations, and microparticle delivery systems. The pharmaceutical excipients include starch, dextrin, sodium polymethyl cellulose, magnesium stearate, and talc. The product is selected from pharmaceuticals and health products.

[0018] The present invention therefore also relates to the use of pharmaceutical compositions with chlorogenic acid as the active ingredient in the prevention, relief, and / or treatment of autoimmune demyelinating diseases. The pharmaceutical compositions can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be formulated by combining this compound with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0019] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit doses via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc. The dosage form can be liquid, solid, or semi-solid. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including O / W, W / O, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc. The compounds of this invention can be formulated into conventional formulations, as well as sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0020] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets. To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formulated into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The various diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention. To formulate the compounds of the present invention into injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, cosolvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. When preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents. Furthermore, if necessary, colorants, preservatives, flavorings, tasters, or other additives can be added to the pharmaceutical preparation. To achieve the intended therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered using any known method of administration.

[0021] Beneficial technical effects

[0022] 1. The chlorogenic acid of the present invention can prevent, alleviate and / or treat autoimmune demyelinating diseases, providing a new structural type of drug option for the clinical treatment of autoimmune demyelinating diseases.

[0023] 2. The chlorogenic acid of this invention can achieve therapeutic and preventative effects with oral administration and small doses. The drug is safe and reliable. Its development as a drug has significant advantages. Attached Figure Description

[0024] Figure 1 Effects of chlorogenic acid on body weight in EAE mice. In this experiment, the body weight of mice in the EAE model group was significantly lower than that of the normal control group after the onset of the disease. After administration, compared with the model group, the body weight of the chlorogenic acid treatment group increased in the later stage of administration.

[0025] Figure 2 Effects of chlorogenic acid on disease scores in EAE mice. In this experiment, the disease scores of mice in the EAE model group were significantly higher than those in the normal control group after the onset of the disease. After administration of chlorogenic acid, the overall symptoms of mice in the chlorogenic acid-treated group were alleviated, and their disease scores were significantly lower than those in the EAE model group, showing a significant improvement effect on disease scores. This confirms that chlorogenic acid has a significant effect on improving the neurological function of EAE mice.

[0026] Figure 3 Effect of chlorogenic acid on suspension time in EAE mice. In this experiment, compared with the normal control group, the suspension time of EAE model mice on wire mesh was significantly reduced. Chlorogenic acid could prolong the suspension time of EAE mice, confirming that chlorogenic acid treatment has a significant effect on improving the motor function of EAE mice. ### P < 0.001 vs. normal control group, ***P < 0.001 vs. EAE model group.

[0027] Figure 4 Effects of chlorogenic acid on suspension grading in EAE mice. In this experiment, compared with the normal control group, the suspension scores of EAE model mice were significantly reduced after the onset of the disease. After administration of chlorogenic acid, the suspension scores of EAE mice in the chlorogenic acid-treated group were significantly increased compared with the EAE model group. ## P < 0.01 vs. normal control group; **P < 0.01, ***P < 0.001 vs. EAE model group.

[0028] Figure 5 Effects of chlorogenic acid on inflammatory cell infiltration in the spinal cord of EAE mice. In this experiment, compared with the normal control group, the spinal cord of EAE model mice showed significant inflammatory cell infiltration, and chlorogenic acid could significantly reduce the infiltration area of ​​inflammatory cells.

[0029] Figure 6 The effect of chlorogenic acid on demyelination of the spinal cord in EAE mice. In this experiment, after LFB staining, compared with the normal control group, the spinal cord of mice in the EAE model group showed demyelination lesions with a larger area. Chlorogenic acid can reduce the area of ​​white matter whitening in the spinal cord, effectively improving the demyelination situation. Detailed Implementation

[0030] The following description, in conjunction with the present invention, further illustrates the pharmacological effects of chlorogenic acid and its pharmacologically acceptable salts in the prevention, relief, and / or treatment of autoimmune demyelinating diseases.

[0031] The following embodiments illustrate the invention in more detail, but are not intended to limit the invention in any way.

[0032] Example 1: The effect of chlorogenic acid on the behavior of EAE mice

[0033] 1.1 Establishment and drug administration of an experimental autoimmune encephalomyelitis mouse model

[0034] Experimental Principle

[0035] C57BL / 6J mice were treated with MOG 35-55 Induced EAE model.

[0036] Experimental methods

[0037] Female C57BL / 6J mice, 6 weeks old, weighing 16-18g, were subcutaneously injected with MOG after 3-5 days of acclimatization feeding. 35-55 An experimental autoimmune encephalomyelitis (EAE) animal model was established by intravenous injection of 300 μg of pertussis toxin and 400 ng of pertussis toxin. A normal control group was also set up. Eleven days after modeling, the animals began to show symptoms, exhibiting varying degrees of limb paralysis, confirming the successful establishment of the mouse model of experimental autoimmune encephalomyelitis.

[0038] Female C57BL / 6 mice were randomly divided into two groups after immunization: an EAE model group and an EAE + 100 mg / kg chlorogenic acid treatment group. Starting 14 days after modeling, chlorogenic acid was administered once daily by gavage. The normal control group and the EAE model group received the same volume of solvent control (0.5% sodium carboxymethyl cellulose solution). Chlorogenic acid was continuously administered until day 28 after immunization. Animal weight and disease scores were measured daily, and mortality was recorded. Suspension grading was measured on days 7, 14, 21, and 28 post-immunization, and the suspension time on the wire mesh was measured on day 28.

[0039] Experimental results

[0040] The animals began to show symptoms on day 11 after immunization, including weight loss and decreased neurological function scores.

[0041] 1.2 Effects of chlorogenic acid on body weight in EAE mice

[0042] Experimental methods

[0043] Body weight is an important indicator of an animal's energy balance and growth. In this experiment, we observed and recorded the animals' activity level, coat condition, and other general characteristics daily, and monitored their body weight daily.

[0044] Experimental results

[0045] In this experiment, the body weight of mice in the EAE model group was significantly lower than that of the normal group after the onset of the disease. However, compared with the model group, the body weight of mice in the chlorogenic acid treatment group increased in the later stage of drug administration, confirming that chlorogenic acid has the effect of improving weight loss. Results are shown below. Figure 1 .

[0046] 1.3 Effects of chlorogenic acid on disease scores in EAE mice

[0047] Experimental methods

[0048] After modeling, the experimental mice were scored daily using the following criteria:

[0049] 0 points: Normal mouse; 0.5 points: Tail weakness; 1 point: Complete tail paralysis; 1.5 points: One hind limb weakness; 2 points: Both hind limbs weakness; 2.5 points: One hind limb paralysis and the other hind limb weakness; 3 points: Both hind limbs paralysis; 3.5 points: Partial forelimb weakness; 4 points: Partial forelimb paralysis; 4.5 points: Complete forelimb paralysis; 5 points: Death.

[0050] Experimental results

[0051] In this experiment, the disease score of the EAE model group mice was significantly higher than that of the normal control group after the onset of the disease. After administration of chlorogenic acid, the overall symptoms of the disease in the chlorogenic acid-treated group were alleviated, and the disease score was significantly lower than that in the EAE model group, showing a significant improvement effect on the disease score. This confirms that chlorogenic acid has a significant improving effect on the neurological function of EAE mice. Results are shown below. Figure 2 .

[0052] 1.4 Effect of chlorogenic acid on suspension time in EAE mice

[0053] Experimental methods

[0054] On day 28 after modeling, the time it took for mice to fall from a 180° wire mesh was measured; a time greater than 120 seconds was counted as 120 seconds.

[0055] Experimental results

[0056] In this experiment, compared with the normal control group, the suspension time of EAE model mice on the wire mesh was significantly reduced. Chlorogenic acid could prolong the suspension time of EAE mice, confirming that chlorogenic acid treatment has a significant improving effect on the motor function of EAE mice. Results are shown below. Figure 3 And Table 1.

[0057] Table 1. Effect of chlorogenic acid on suspension time in MOG-induced EAE mice.

[0058]

[0059] Mean±SEM (n=6).

[0060] ### P < 0.001 vs. normal control group, ***P < 0.001 vs. EAE model group.

[0061] 1.5 Effects of chlorogenic acid on suspension grading in EAE mice

[0062] Experimental methods

[0063] On days 7, 14, 21, and 28 after modeling, the mice's forepaws were suspended from a balance rope 30 cm above the ground. The limb suspension status of the mice on the balance rope was observed and scored. The grading criteria were as follows: 5 points: Grasping the rope and able to pull with the hind limbs, with the tail tightly wrapped around the rope; 4 points: Grasping the rope and able to pull with the hind limbs, with the tail raised but not wrapped around the rope; 3 points: Grasping the rope and able to pull with the hind limbs, with the tail drooping; 2 points: Raising the hind limbs and grasping the rope but unable to pull; 1 point: Raising the hind limbs but unable to grasp the rope; 0 points: Unable to raise the hind limbs.

[0064] Experimental results

[0065] In this experiment, compared with the normal control group, the suspension score of EAE model mice was significantly reduced after the onset of the disease. After administration, the suspension score of EAE mice in the chlorogenic acid administration group was significantly increased compared with the EAE model group, confirming that chlorogenic acid can significantly improve the suspension behavior of EAE mice. Results are shown below. Figure 4 And Table 2.

[0066] Table 2. Effects of chlorogenic acid on suspension grading in MOG-induced EAE mice.

[0067]

[0068] Mean±SEM (n=6).

[0069] ### P < 0.001 vs. normal control group; **P < 0.01, ***P < 0.001 vs. EAE model group.

[0070] Example 2: Effects of chlorogenic acid on inflammatory cell infiltration and demyelination in the spinal cord of EAE model mice

[0071] 2.1 Establishment of the EAE mouse model and drug administration

[0072] The experimental principle, experimental method, and experimental results are the same as in Example 1.1.

[0073] 2.2 Effects of chlorogenic acid on inflammatory cell infiltration in the spinal cord of EAE mice

[0074] Experimental methods

[0075] On day 28 after modeling, three mice from each group were anesthetized with 4% tribromoethanol. The mice were first perfused with physiological saline until the liver turned white, then perfused with 4% paraformaldehyde until the limbs stiffened. The mice were then decapitated, and the lumbar enlarged portion of the spinal cord was fixed in 4% paraformaldehyde. Paraffin sections of the lumbar enlarged portion of the spinal cord were prepared and stained with hematoxylin and eosin (H&E) to observe the infiltration of inflammatory cells in the spinal cord.

[0076] Experimental results

[0077] In this experiment, compared with the normal control group, the EAE model group mice showed significant infiltration of inflammatory cells in the spinal cord. Treatment with 100 mg / kg chlorogenic acid significantly inhibited the infiltration of inflammatory cells in the spinal cord of EAE mice, and the pathological changes such as fibrosis and vacuolation caused by inflammatory infiltration were significantly improved, confirming that chlorogenic acid can significantly improve inflammatory cell infiltration in the spinal cord of EAE mice. Results are shown below. Figure 5 .

[0078] 2.3 Effects of chlorogenic acid on demyelination in the spinal cord of EAE mice

[0079] Experimental methods

[0080] On day 28 after modeling, three mice from each group were anesthetized with 4% tribromoethanol. The mice were first perfused with physiological saline until the liver turned white, then perfused with 4% paraformaldehyde until the limbs stiffened. The mice were then decapitated, and the lumbar enlargement of the spinal cord was fixed in 4% paraformaldehyde. Paraffin sections of the lumbar enlargement of the spinal cord were prepared and stained with Fast Blue (LFB) to observe the demyelination within the spinal cord.

[0081] Experimental results

[0082] In this experiment, after LFB staining, compared with the normal control group, the spinal cord of EAE model mice showed demyelinating lesions with a larger area. 100 mg / kg chlorogenic acid could reduce the area of ​​white matter in the spinal cord of EAE mice, effectively improving the demyelination condition. Results are shown below. Figure 6 .

Claims

1. The use of chlorogenic acid and / or its pharmacodynamically acceptable salts as shown in formula (I) in the preparation of medicaments for the prevention, relief and / or treatment of autoimmune demyelinating diseases; 2. The application according to claim 1, characterized in that, The autoimmune demyelinating diseases include demyelinating autoimmune diseases of the central nervous system and demyelinating autoimmune diseases affecting the peripheral nervous system.

3. The application according to claim 2, characterized in that, The aforementioned demyelinating autoimmune diseases of the central nervous system include multiple sclerosis, neuromyelitis optica spectrum disorders, acute disseminated encephalomyelitis, leukoencephalitis, and transverse myelitis. Demyelinating autoimmune diseases affecting the peripheral nervous system include acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, motor and sensory neuropathy, genetic sensorimotor neuropathy, peroneal muscular atrophy, and progressive neurogenic peroneal muscular atrophy.

4. The application according to claim 3, characterized in that, The multiple sclerosis includes relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and progressive-relapsing multiple sclerosis.

5. The use of a pharmaceutical composition in the prevention, relief, and / or treatment of autoimmune demyelinating diseases, characterized in that, The pharmaceutical composition contains an effective dose of chlorogenic acid as shown in formula (I), and optionally a pharmaceutically acceptable excipient; 6. The application according to claim 5, characterized in that, The pharmaceutical composition contains other active ingredients in addition to chlorogenic acid and / or its pharmaceutically acceptable salts as active pharmaceutical ingredients.

7. The application according to any one of claims 5-6, characterized in that, The pharmaceutical compositions include the following dosage forms: solutions, suspensions, lyophilized powder for injection, emulsions, pills, capsules, powders, controlled-release, sustained-release formulations, and microparticle delivery systems.

8. The application according to claim 5, characterized in that, The pharmaceutical excipients include starch, dextrin, sodium polymethyl cellulose, magnesium stearate, and talc.

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