TW200948363A - Piperazine-based CCR5 antagonist tablet dosage form - Google Patents

Abstract

Tablets containing 1-[(4, 6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-methoxy-1(R)-[4-(trifluoromethyl)phenyl]ethyl]-3-(S)-methyl-1-piperazinyl]-4-methyl-piperidine or a pharmaceutically acceptable salt thereof are disclosed. Methods of making such tablets with satisfactory processability are also disclosed. In addition, methods for treating HIV as well as inflammatory diseases with an antagonist of chemokine (C-C motif) receptor 5 (CCR5) are disclosed.

Description

200948363 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to the inclusion of W(4'6_: f-group·5•(tetra)-based postgroup] o-[2-methoxy-i (RH4_(three gas) a phenyl]ethyl]ethyl]-3,-methyl-cyano-M-methyl-pyrene or a pharmaceutically acceptable salt thereof. The present invention also relates to the use of such tablets for the treatment of human immunity Methods of lacking viral (HIV) infections and inflammatory diseases and methods of preparing such tablets. [Prior Art] The discussion or citation of the documents referred to herein should not be construed as an admission that such references are prior Technology. The global health crisis caused by HIV, the pathogen of acquired immunodeficiency syndrome (AIDS), is undoubted, and although recent advances in drug therapy have successfully slowed AIDS progression, given the emergence of known drug-resistant HIV strains As well as a growing number of drug-resistant patients, new drug therapies are still needed. In practice, by 2004, in countries with extensive antiretroviral access, up to 20% of newly infected individuals Drug-resistant HIV Strain. Similarly, based on one or more anti-reverses in different anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) Results of the resistance test for viral viruses 'The emergence of drug-resistant HIV strains has produced customized drug therapies for individual patients, the so-called "optimized background therapy" (OBT). In addition, 'the need for greater patient convenience and improvement Compliance with more versatile drug therapies (eg, oral, solid dosage forms, low pill burden, long-term or twice-a-day regimen, minor adverse effects) to reduce 139805.doc 200948363 to produce new resistant HIV strains Possibly. The chemotactic hormone (CC major structure) receptor 5 (CCR5) gene has been reported to play a role in combating HIV infection. HIV infection is caused by the interaction of the cell receptor CD4 with the second chemokine co-receptor molecule. The virus begins to attach to the target cell membrane, and then the infected cells replicate and spread the infected cells via blood and other tissues. There are various chemokine receptors, but for giant pythons In the case of macrophage-tropic HIV, the key pathogenic virus strain that is secreted in vivo in the early stage of infection, the major chemokine receptor required for HIV to enter cells is CCR5. Therefore, interference in the viral receptor The interaction with CCR5 blocks HIV entry into host cells. Furthermore, because CCR5 antagonists target the extracellular mechanisms of HIV, they are less likely to produce resistant HIV strains and are more likely to be effective against current resistance. HIV strains, such currently resistant HIV strains, overcome the intracellular mechanisms of anti-retroviral action against HIV. CCR5 has also been reported to mediate cell metastasis in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies. Therefore, antagonists of CCR5 are suitable for the treatment of such diseases and for the treatment of other inflammatory diseases or conditions, such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft versus host disease. 1-[(4,6-Dimercapto-5-pyrimidinyl)carbonyl]-4-[4-[2-decyloxy-l(R), which is referred to herein as Compound I, is represented by the following chemical structure. -[4-(Trifluoromethyl)phenyl]ethyl]-3-(S)-indolyl-1-piperidinyl]-4-methyl-piperidine: 139805.doc 200948363

❹ or its pharmaceutically acceptable salt is disclosed in U.S. Patent No. 6,391,865 (see, for example, lines 24 to 25 and lines 35 to 116, Example 29A). The anti-5 antagonists disclosed in this document are incorporated herein by reference. This CCR5 antagonist is effective in blocking ligand binding and body signaling on human cells with the chemokine receptor CCR5. Conclusion * ° In addition, it inhibits the infection of primary cells through the HIV-1 isolate using this receptor by inhibiting viral fusion and entry. [[4,6-Dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-Methoxy-1(R)_[4_(trifluoromethyl)phenyl]ethyl]_3_ Q (s)_methyl-1-piperidyl 11] Mercapto-piperidine or a pharmaceutically acceptable salt thereof (also known as "Vick Vero ("^"(")", "§(:11 417690" and "8匸11 D") In a late clinical trial in combination with one or more other antiretroviral agents for oral administration to HIV-infected patients. [Summary of the Invention] The objective is to meet the need for effective drug therapy while reducing the possibility of drug-resistant mv strains. Sex' inevitable Develop a pharmaceutical dosage form that promotes patient compliance (eg 'oral, solid dosage form, low pill burden, two doses of 泠 139 805.doc 200948363 twice daily.) In general, oral solid dosage forms are easy for patients It is preferred to administer and handle and store. In particular, tablets provide the active pharmaceutical ingredient in a minimum amount per dosage unit, thereby reducing the burden of the pill in terms of the number and size of individual units required to administer an effective amount per day. In addition, in order to meet the needs of a population of HIV-positive patients with increased benefits and to reduce the financial burden associated with patient care, it is valuable to develop such drugs that permit easy and reliable mass production (with satisfactory commercial processability). Stable manufacturing method of the dosage form. SUMMARY OF THE INVENTION The present invention satisfies the above objects or needs for a solid dosage form suitable for the orally administered compound j or a pharmaceutically acceptable salt thereof, and a robust manufacturing method for its manufacture. The present invention provides a lozenge suitable for oral administration, characterized in that at most 20% of the W/W compound is negatively pharmaceutically acceptable. The tablet of the present invention comprises granules suitable for use in the ingots comprising a compound or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the agent of the present invention provides for the treatment of sputum using a once-a-day dosing regimen. A sufficiently advantageous pharmacokinetic parameter for a compound of V! or a pharmaceutically acceptable salt thereof. These lozenges provide suitable pharmacokinetic properties for infections in patients treated with an optimized background treatment. These (4) are also suitable for the treatment of inflammatory diseases. The present invention also provides a robust manufacturing method which allows easy and reliable preparation of a large number of key agents of the present invention having satisfactory commercial processability. 139805.doc 200948363 Details. The present invention provides a high shear wet granulation method which produces a large "= satisfactory processability" in the tablet which exhibits excellent powder flow without sticking to the surface of the tool and from the hopper. In one aspect, the present invention provides a tablet comprising granules for oral administration, the granule comprising Compound j or a pharmaceutically acceptable salt thereof and a mixture, a disintegrant and a diluent Wherein the compound "Geqi Medicine: an acceptable salt constitutes from 10% by weight to 20% by weight of the tablet. In the examples, the pharmaceutically acceptable salt of the compound is citric acid hydrochloride, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, antibutanic acid, and butyl Acid addition salts of diacids, ascorbic acid, cis-butyl di-acids, or other inorganic acids and tick-acids well known in the art. In a preferred embodiment, the compound is pharmaceutically acceptable. The acceptable salt is an acid addition salt formed using cis-butane diacid, i.e., the maleic acid salt of Compound I. In certain preferred embodiments, the amount of the compound hydrazine or pharmaceutically acceptable salt hydrazine is equivalent to 24.6 mg of the compound [the free base. In a preferred embodiment, the pharmaceutically acceptable salt of Compound I is a maleate at a dose of 30 mg. In certain embodiments, the binder is microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural gum, synthetic gum, polyvinylpyrrolidone or povidone (PVP), pregelatinized Starch, HPC, HPMC, or a combination of two or more thereof. In a preferred embodiment, the binder is PVP. In certain embodiments, the disintegrant is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone 139805.doc 200948363 (Cr〇Sp〇vid 〇ne) or a salt thereof, thioglycolic cellulose, microcrystalline cellulose, HPC substituted with one to six carbon alkyl groups, starch, pregelatinized starch, alginic acid: or a combination of two or more thereof. In a preferred embodiment, the disintegrant is a cross-linked carboxyindole cellulose salt. In certain embodiments, the diluent is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, house powder, dehydrated beta calcium phosphate, or both Combination of the two or more, Q In the preferred embodiment, the diluent is microcrystalline fiber h. In another preferred embodiment, the diluent is a combination of microcrystalline cellulose and lactose monohydrate. In another embodiment, the tablet further comprises an extragranular (tetra) oxime (iv) excipient such as a diluent, a disintegrant, a lubricant, or a combination of two or more thereof. In another embodiment, the tablet additionally comprises an extragranular excipient which is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, anhydrous dibasic Calcium phosphate or a combination of two or more thereof. In a preferred embodiment, the tablet further comprises an extragranular excipient which is microcrystalline cellulose. In certain embodiments, the bond further comprises an extragranular excipient which is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, crospovidone or A salt thereof, a methyl cellulose, a microcrystalline cellulose, a HPC substituted with a hexacarbon alkyl group, a starch, a pregelatinized starch, a sodium alginate or a combination of two or more thereof. In a preferred embodiment, the tablet additionally comprises an extragranular excipient which is a parent-linked buffered cellulose salt. In certain embodiments, the tablet further comprises an extragranular excipient which is a stearin 139805.doc 200948363 magnesium sulphate, calcium stearate, Λ^ 硬 酸 acid, stearin anti-butenyl sulphate Or a combination of two or seven & sodium butyrate, laurel, or a combination of two or more. In one, the tablet additionally comprises an extragranular excipient which is a hard acid. Examples In some embodiments, the compound I or its pharmaceutically acceptable asleep composition is 20 weight percent. /η β - Pasture and asphyxiation In the consistent application, the particles constitute ingots from 70% to 70% by weight. In the * 〇 ^ embodiment, the binder constitutes from 2% by weight to 8% by weight of the tablet. In one embodiment, the disintegrant constitutes from 5% by weight of the tablet to 6% by weight. %. In the embodiment, the diluent constitutes from 6% by weight to 7% by weight of the tablet. . In one embodiment, the lubricant constitutes 0.25% by weight of the tablet. In an embodiment, the tablet additionally comprises a surfactant, a slip agent, or a combination of two or more thereof. In another aspect, the invention provides a compound comprising! Or a granule lozenge of a pharmaceutically acceptable salt thereof, when administered to a patient once a day in an optimized dosing regimen containing pi/r, equivalent to a free agent of 24 6 mg of the compound, It provides an average steady state AUC of compound j of about 621 〇ng_hr/mi. The present invention also encompasses similarly bioavailable lozenges such that when administered in an optimal background regimen containing ΡΙ/r to a patient once a day at a dose equivalent to 24 6 mg of the free base of Compound I, the relative The average steady state AUC range is from 80% to 125% of 6210 ng-hr/ml, i.e., in the range of from about 4968 ng-hr/ml to about 7763 ng-hr/ml. In one embodiment, the suspect provides at least 621 ng-hr/ml when administered to the patient once a day at a dose equivalent to 24.6 mg of Compound I in an optimized background treatment with ΡΙ/r. 80%, that is, an average steady-state AUC of Compound I of at least 4968 ng-hr/ml. In certain embodiments, the key is provided at least once a day at a dose equivalent to 24.6 mg of Compound I free of dose to the patient in a background treatment regimen containing pi/r optimized 139805.doc -9-200948363 The average steady state AUC of Compound I at 6210 ng-hr/ml. In another aspect, the present invention provides a tablet comprising a granule of Compound I or a pharmaceutically acceptable salt thereof, which is administered to a patient once a day at an equivalent to 24.6 mg in an optimized background treatment with ΡΙ/r When administered as a free dose of Compound I, it provides an average steady state Cmin of Compound I of at least 200 ng/mL. In a preferred embodiment, the bond: the agent is administered once a day. In another embodiment, the tablet is administered twice a day. In one embodiment, the lozenge is administered in a range of from about 1 hour to about 3 hours when administered to the patient once a day at a dose equivalent to 24.6 mg of Compound I in an optimized background treatment with ΡΙ/r. An average steady state Cmax of Compound I of at least 297 ng/mL is provided at an average Tmax. In one embodiment, the lozenge provides about 372 ng/mL of Compound I when administered to the patient once a day at a dose equivalent to 24.6 mg of Compound I in an optimized background treatment with ΡΙ/r. Average steady state Cmax. The present invention also encompasses bioavailable lozenges such that the relative average stability of Compound I is administered to a patient once a day at a dose equivalent to 24.6 mg of Compound I free base in an optimized background regimen containing ΡΙ/r. State Cmax is within 80% to 125% of 372 ng/ml, i.e., in the range of from about 297 ng/mL to about 465 ng/mL. In one embodiment, the key provides 297 ng/ml when administered to the patient once a day at a dose equivalent to 24.6 mg of Compound I free of assays in an optimized background regimen containing ΡΙ/r. In one embodiment, the lozenge provides at least one dose equivalent to 139805.doc -10-200948363 24.6 mg of the free base of Compound I once a day in an optimized background regimen containing ΡΙ/r. The average steady-state AUC of Compound I at 372 ng/ml. In certain preferred embodiments, the amount of Compound I or a pharmaceutically acceptable salt is equivalent to 24.6 mg of the free base of Compound I. In one embodiment, the pharmaceutically acceptable salt of Compound I is a maleic acid salt at a dose of 30 111 §. In certain embodiments, the particles additionally comprise a binder, a disintegrant, and a diluent. In one embodiment, the granules are prepared by a process comprising: (a) dry blending: (i) Compound I or a pharmaceutically acceptable salt thereof; and (1) a disintegrant and a diluent Providing a first dry blending powder; (b) using a granulating solution comprising water and a binder to make the step "&"

Preparing the first dry blended powder in a high shear granulator; (4) forming wet wet granules by wet grinding the cohesive prepared in step "b"; (d) by drying from Step "^" wet grinding the particles to form dry tan particles; and (4) dry grinding the dried particles from step "d". Those skilled in the art should understand that the granulation solution range will vary according to the batch size: the best of the sheep is towards ^ m ^ ^ 4d. ^ ^ The straw is determined by routine experimentation. In one embodiment of the seal test, the target spray rate of the valley liquid is in the range of about 139805.doc 200948363 270 g/min to about 390 g/m. In another embodiment, the granulation solution target spray rate is about 330 g/min. In the experimental scale batch 2 embodiment, the target wet stacking time is in the range of from about 3 seconds to about 6 minutes. In another embodiment, the target wet stacking time is in the range of from about % seconds to about 4 minutes. In another embodiment, the target wet stacking time is about 1 minute. In one aspect, the invention provides a method of treating HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a lozenge of the invention: any one. In an embodiment, the method additionally comprises administering at least an H anti-retroviral agent.心, ϋ In a heart, the invention provides a method of treating HIV infection in a patient' which comprises administering to a patient in need thereof a therapeutically effective amount of any of the agents of the invention and an antiretroviral regimen. In a preferred embodiment, the 'treatment' is to optimize the background treatment. In one aspect, the invention provides a method of treating HIV infection in a patient with an optimized background treatment comprising PI/r comprising administering to a patient in need thereof a therapeutically effective amount of a lozenge of the invention Either. In an embodiment 0, 3 has an optimized background treatment of PI/r comprising darunavir. In certain embodiments, darunavir is administered twice daily (BID) in a dose of 嶋mg. In one embodiment, the patient has not received antiretroviral therapy (treatment na_ive). In another embodiment, the patient has experienced antiretroviral therapy. In one aspect, the invention provides a method of treating HIV infection in an adult patient who has undergone antiretroviral therapy, comprising co-injecting an adult patient with an antiretroviral effect of 139805.doc -12-200948363 In combination with any of the therapeutically effective agents and the PI/P^ reading:-state, the present invention provides a method of treating an inflammatory disease, comprising administering to a patient in need thereof a therapeutically effective amount of a key agent of the present invention Any of them. [Embodiment] 2 The present invention described in the above description of the present invention can be fully understood. It is to be understood that all of the technical and scientific terminology techniques used in the present invention (as claimed in the present invention) are generally understood to have similar or equivalent methods and materials as may be used in the practice or testing of the present invention. However, the materials, methods, and examples are illustrative only, and are not intended to be limiting. All other documents in this document are incorporated by reference in their entirety. Patent and Technology 2 "Vickeway "Ro" means H(4,6-dimercapto)dimethoxy-'fluorenyltrifluoromethyl)phenyl]ethyl]-, methyl-piperidin or a pharmaceutically acceptable salt thereof. Including the inhibitor/ritonavir (rit_·^^ Γ: treatment of protease inhibitors. For example, including: the combination of the inhibitor of darunavir and ritonavir in a course of treatment. The diritonaline is administered twice as a protease, ie, below 600 (for example, _mg/139805.doc -13-200948363 "AUC" when used in this article, from the active agent The parameter of the cumulative plasma concentration of plasma for any given active agent and the face-to-time curve under the concentration-time curve, and == indicates the expiration of the active agent over time. Unless the time is otherwise ashamed, the total amount of the tongue agent and the available H to the 24 hour hour is considered to cover 0. When the blood is used herein, the maximum observation of the active agent means for a given active agent. Pre-dose (0

Cmin" is the lowest plasma concentration for use in hr) herein. Means the time from the granulation solution to the dry blending of the first or more of the term "wet stacking time" as used herein and the end of the cohesive step, between a powder and the granulation solution. Mix. Surgery; /αtherapy "Thinking means reducing or alleviating - or disease-related symptoms. The compounds are described in U.S. Patent No. 6,391,865 (e.g., Ref. No., lines 24 to 25 and lines 35 to 116, Example 29), which is incorporated by reference in its entirety. Preparation of hydrazine and its pharmaceutically acceptable salts. A specific method for preparing (particularly) the cis-butane salt of Compound I is disclosed in U.S. Patent No. 6,943,251, the disclosure of which is incorporated herein in its entirety. In the examples, the pharmaceutically acceptable salt of the compound is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, and butyl. Diacids, ascorbic acid, cis-butanedioic acid, sulphuric acid sulfonic acid or other inorganic acids well known in the art and acid addition salts formed by 139805.doc -14·200948363 acid. In a preferred embodiment, the pharmaceutically acceptable salt of the compound is an acid addition salt formed using maleic acid. Examples of pharmaceutically acceptable salts of Compound I include, but are not limited to, acetate, besylate, benzoate, bicarbonate, bromide, calcium edetate, camphor sulfonate, carbonic acid Salt, chloride/dihydrochloride, citrate, hydrazine, bismuth-di(hydrogenated rosin) ethylenediamine, ethylenediaminetetraacetate, 1,2-ethanedisulfonate, ethanesulfonate Acid salt, fumarate, glucoheptanoate, gluconate, glutamate, p-glycollamidophenylarsonate, hexylisophthalate , hypoclate, hydrogen desert acid salt, hydrochloride, 2-acetone sulfonate, hydroxynaphthoate, iodide, lactate, lactoblate, lauryl sulfonate , malate, maleate, mandelate, methanesulfonate, methyl bromide, sulfhydryl nitrate, sulfhydryl sulfate, mucic acid salt, nafate, naphthalene sulfonate , nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, sodium succinate, stearate, Acetate, succinate, sulphate, tosylate, tannate, tartrate/tartrate, 8-chlorotheophyllinate, triethiodide ), adipate, alginate, amine salicylate, dehydrated methylene citrate, arecoline, aspartate, hydrogen sulfate, butyl bromide, camphorate, Digluconate, dihydrobromide, disuccinate, glyceride, hemisulfate, hydrofluoride, hydrogenate, methylene bis (salicylate), naphthalene Sulfonate, oxalate, pectate, persulfate, phenylethyl barbiturate, picrate, propionate, sulfur 139805.doc 15 200948363 cyanate, undecanoic acid Salt, acetamidoacetate, N-ethyl _L_ aspartame, N-acetyl sulphate, adamantate, adipate, hydrazine alkyl sulfonate , 蒽醌-1,5-disulfonate, arabolactansulfate, arginine, aspartate, betaine, carnitine, 4-chlorom-benzenesulfonate, Citrate Diethyl sulfonate, acetophenethylamine, diammoniumamine, diguaiacylphosphate, dioctyl sulfosuccinate, diperate, fructose-1 , 6-diphosphate, glucose phosphate, L_glutamate, naphthoate, lauryl sulfate, lysine, 2-naphthoate, octanoate, tannic acid and Cocoa Bean Acetate. In a preferred embodiment, the pharmaceutically acceptable salt of Compound I is maleate. Lozenges In a particular embodiment, the present invention provides a lozenge dosage form comprising a binder comprising a) Compound I or a pharmaceutically acceptable salt thereof; b) a binder; c) a diluent; d) Disintegrant. In certain embodiments, the lozenge can include additional binders, diluents, and/or disintegrants. In certain embodiments, the tablet comprises particles' such particles comprise Compound I or a pharmaceutically acceptable salt thereof; a binder; a diluent; and a disintegrant. In certain embodiments, the particles constitute from 65% to 75% by weight of the bonding agent. In some of these embodiments, and independently or in combination with the weight percent of the granules, the granules comprise from 25% to 33% by weight of the compound! Or a pharmaceutically acceptable salt thereof, a dilution of 60% to 70% by weight! From about 6% by weight of the disintegrant and from 2% by weight to 8% by weight of the binder. In certain embodiments, the tablet contains at least 10% by weight of the compound! Or a pharmaceutically acceptable salt thereof. 139805.doc •16· 200948363 In certain embodiments, the lozenge comprises about 2% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the tablet additionally comprises an extragranular composition comprising one or more diluents, one or more disintegrants, one or more lubricants, or a combination of two or more thereof.

Adhesives are generally used to impart a good adhesion to a tablet dosage form. Examples of binders include, without limitation, microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural gum, and <gelatin, povidone (pVp), pregelatinized powder, Hpc, and eight Or a combination of both. In a preferred embodiment, the binder is povidone. The binder may constitute about 2 parts by weight of the tablet. Up to 8 weight. /. , such as 3 / 〇 to 5 / ❶, and usually only in the form of particles. In a preferred embodiment, the binder is povidone and is present at about 4% by weight of the tablet. Examples of the detoxifying agent include, but are not limited to, sodium starch glycolate, carboxymethyl fibrin, including its sodium salt and 35 salt; cross-linked stearyl cellulose, including salts thereof, such as cross-linked sodium methacrylate; Cross-linked povidone, including its sodium salt; methyl cellulose; microcrystalline (tetra); Hpc substituted by - to hexanyl; temple: 'pregelatinized starch; sodium alginate; and both or both In the preferred embodiment, the disintegrant is a crosslinked buffered cellulose salt. The disintegrant may comprise from about 1% to about 25% by weight of the tablet, or more usually from about 1% to about 6% of the tablet. In the preferred embodiment of the button, the disintegrating agent is about 4% by weight of the tablet. In certain embodiments, from 25% to 75% by weight of the disintegrant is particulate and from 25% to 75% by weight of the disintegrant is extragranular. In a special embodiment, 40% by weight to 6 〇 〇 牙 牙 牙 υ υ υ υ υ υ υ υ υ υ υ υ υ υ υ υ υ 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且The disintegrant is between the particles of the tablet and the extra-granular portion of the tablet. In a preferred embodiment, about 139805.doc -17-200948363 50% of the disintegrant is present in granular form and about 5% by weight of the disintegrant is present in extragranular form. One or more diluents may form the remainder of the tablet formulation. Examples of diluents include, without limitation, lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, and the like; mannitol; xylitol; dextrose; sucrose; sorbitol; Cellulose; starch; dihydrated two-price test for the acid-killing mother; and a combination of two or more thereof. The diluent can constitute 40% by weight of the bond. Up to 85% by weight, such as from 5〇% to 75% or from 6〇% to 7〇%. In certain embodiments, the diluent is microcrystalline cellulose, lactose, or a combination of two or more thereof. A preferred mixture of diluents is microcrystalline cellulose and lactose (e.g., lactose monohydrate). In certain embodiments, the lactose is only present in particulate form and the microcrystalline cellulose is present in particulate and extragranular form. In certain such embodiments, the diluent mixture is from 4% by weight to 65% by weight of lactose monohydrate, from 5% by weight to 10% by weight of particulate microcrystalline cellulose and from 2% by weight to 40 to 40 weight 3: % extragranular microcrystalline cellulose composition (ie, the spinner comprises 3% by weight to 45% by weight of lactose monohydrate, 2% by weight to 3% by weight of extragranular microcrystalline cellulose and 2% by weight to 8 wt% granular microcrystalline cellulose).例 Exemplary lozenges of the invention thus comprise from 15% to 25% by weight of: 1 or a pharmaceutically acceptable salt thereof, 35% to 45% by weight of lactose monohydrate, 25% to 35 weight % microcrystalline cellulose, 2% to 6% by weight of croscarmellose sodium, 2% to 6% by weight of povidone and 5% by weight to 3% by weight of magnesium stearate. In a preferred embodiment, the tablet of the present invention comprises 2% by weight of Compound I or a pharmaceutically acceptable salt thereof, 4% by weight of lactose monohydrate, 3〇139805.doc •18-200948363 Weight ◦/〇 microcrystalline cellulose (with a particle size to extragranular ratio of about 1 to about 5), 4% by weight of croscarmellose sodium (with a particle size to extragranular ratio of about 1 to about 1) ), 4% by weight of povidone and 2% by weight of magnesium stearate. In a particularly preferred embodiment, the pharmaceutically acceptable salt of Compound I is maleic acid. In addition to the active agent, binder, disintegrant, and diluent, the tablet of the present invention may also include one or more surfactants, slip agents, lubricants, or a combination of two or more thereof.

Examples of suitable surfactants include, without limitation, SLS, polysorbate 80, and combinations of two or more thereof. When present, the surfactant can comprise from about 0.2% to about 5% by weight of the tablet. Examples of suitable slip agents include, without limitation, ceria, talc, and combinations of two or more thereof. When present, the slip agent can comprise from about 0.2% to about 1% by weight of the tablet. Examples of suitable lubricants include, without limitation, magnesium stearate, calcium stearate stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, and combinations of two or more thereof. In the preferred embodiment, the lubricant is a stearic acid town. The lubricant, when present, can comprise from about 25% to about café, or more typically from about 1% to about 3, of the tablet. /. And usually only exist outside the grain. In particular, in some embodiments, it is preferred to supply a film coating to the tablet, preferably comprising a propylmethylcellulose (HPMC based) coating material (such as ^^ Π Green_〇padry „ Film coating. The film coating can be added (for example, by weight to 1% by weight. Generally, the film coating is added in an amount of 4% by weight to 8% by weight. In a preferred embodiment, the film coating is applied. Bond 139805.doc -19- 200948363 Addition of 6% by weight. Preparation of a tablet granulation technique to produce an acceptable salt The invention can be prepared by a variety of suitable wet granulations, including high shear wetness. Lozenges containing Compound I or its pharmaceutically compressible microparticles suitable for use in ingots, as described in Scheme j below:

Process I dry push ·' powder

(b) the granulating solution such that the first dry blended powder from step "a" is in (i) compound I or a pharmaceutically acceptable salt thereof; and (8) a granular excipient (eg, 'diluent, collapsed Decomposition,) to provide the first-dry broadcaster ------------- In the step ' ---------- ' _____ (d) by drying from 歩--- The shoulder-grinding granules are used to form dry granules ___________ ^ blending the following to a uniform - to the tablet machine g from the step V dried (0 conditions, super-grain and thinner, disintegrant For example, a slip agent will be a dry form of Compound I or an exemplary excipient (for example, a diluent, a 7 pharmaceutically acceptable salt, and a crude compound) Blending. In some embodiments, the acceptable salt is sieved through a 1190 μm 139805.doc -20· 200948363 sieve, followed by dry blending. After the first dry push powder is tightly held, the water and the adhesive are packaged. The granulating solution cohesives the powder to produce wet granules 0 such as 'about 23% w/v viscous _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Wet granulation is carried out. The granulation solution target spray rate is in the range of about 270 g/min to about 390 g/mini, which is suitable for the scale of the pilot plant. In another embodiment, (4) The liquid target spray rate is 33 〇g/min. In an embodiment suitable for pilot plant scale, the target wet stacking time is between about 30 seconds and about 6 minutes.

The target wet stacking time in the "in other embodiments" ranged from about 3 sec to about 4 minutes. In another embodiment, the target wet stacking time is about 1 minute. The cohesive body was then wet milled using a COMIL wet mill. • Dry the wet granules after wet grinding. In some embodiments, the wet granules are preferably dried in a fluid bed dryer to a residual moisture content of less than about 2% by weight or less. Next, the dried granules are dry milled, such as via a 16-mesh mesh size, to produce granules. Next, the granules are dry blended with at least one of the extragranular excipients (e.g., diluent, disintegrant, lubricant) to uniformity. This microparticle is suitable for ingot making by a compression tablet machine. The resulting bond formed can be film coated as appropriate. Suitable high shear wet granulators include, without limitation, top mounted high shear granulators, twin screw mixers, planetary mixers, high speed mixers, extruders - spheronizers and the like. For additional discussion of wet granulators, see M. Summers and M. Aulton, Dosage Form Design and Manufacture 25: 364-78 (2nd ed., 2001), the entire disclosure of which is incorporated herein by reference. . 139805.doc •21 - 200948363 'High shear wet granulation is a more robust method compared to fluid bed granulation. Therefore, as a commercial production method for a tablet of Compound I or a pharmaceutically acceptable salt thereof, a high shear wet granulation method is preferred. Tablets prepared by this method may have one or more of the following characteristics. First, tablets prepared by the methods described herein are preferably not adhered to typical manufacturing equipment. By way of example, the tablet of the present invention can be prepared on a typical manufacturing facility without the need to treat the device itself with a slip or lubricant and/or the tablet itself leaving a sufficiently small residual amount of material on the spinning device, which Does not interfere with typical manufacturing methods. Second, the lozenge of the present invention can be prepared irrespective of the particle size of Compound I or its pharmaceutically acceptable salt. For example, in certain embodiments, it is not necessary to monitor or adjust the proportion of particles of Compound I or a pharmaceutically acceptable salt thereof having a diameter of less than 10 microns. Significantly, the particle size distribution of the maleic acid salt of the compound oxime drug substance spans from less than 0.1 μm to more than 500 μηη, indicating a population of non-uniform particles. The maleic acid salt of the compound I is usually present in the form of fines (〇丨丨, primary particles (5-10 μηι) and fused aggregated particles (> 5〇〇μηη). Once crystallized, the drug substance That is, there is a tendency to loosely aggregate after separation and drying. The crystallization process of the drug substance is composed of a plurality of deblocking steps affecting the degree of aggregation of the drug substance. The amount of water present in the crystal slurry is a key factor determining the initial particle size. It must be controlled within a narrow range of 15-2 5% w/w to directly compress the tablet. In addition, direct compression is not suitable for commercial scale manufacturing because it is often observed to adhere to the surface of the tool. Similarly, the roll shows the degree of flaws. It adheres to the surface of the tool and is therefore not suitable for commercial scale manufacturing. Conversely, it has been surprisingly found that a wide particle size distribution can be processed into a cis-butanol salt of 139S05.doc • 22· 200948363 Suitable for particulate matter by high shear wet granulation ingots which do not stick to the surface of the tool after the tablet I has been shrinked. Significantly, the figure! is shown by the high shear wet granulation method. Illustrative examples of process flows for the maleic acid salt of Compound I. Combination Therapy The tablet of the present invention can be used in combination with - or a variety of other anti-retroviral agents suitable for use in therapy. Compound j or a pharmaceutically acceptable t salt thereof is combined with - or a plurality of other antiretroviral agents in a single dosage form. 〇 &, Compound 1, or a pharmaceutically acceptable salt thereof, may be combined with one or more other The antiretroviral agent is administered in the same day or sequentially as a separate dosage form. The antiretroviral agent used in combination with the vekeweiro of the present invention comprises one or more core or nucleoside reverse transcriptase inhibitors, Non-nuclear #reverse transcriptase inhibition. 胄, protease inhibitors, viral fusion inhibitors, integrase inhibitors and other anti-retroviral agents that do not fall into these categories. In other words, the inclusion is called HAART (highly active anti-reverse) The combination of transcriptional virus therapy) is combined with sputum sputum or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention encompasses an optimized background treatment with Pi/r to Hiy infection or HIV/ HCV same Infected patients are administered once a day to any of the present invention. The term "nucleoside and nucleotide reverse transcriptase inhibitor" ("Nrti") as used herein means nucleoside and nucleotide and An analogue thereof that inhibits the activity of a torsion reverse transcriptase (an enzyme that catalyzes the conversion of viral genomic HnM RNA to proviral HIV-1 DNA). Typical suitable NRTIs include, but are not limited to, zidovududine 139805 .doc -23- 200948363 (AZT, RETROVIR®); goosine (ddl, VIDEX®); zalcitabine (ddC, HIVID®); stavudine (d4T, ZERIT®) ); lamivudine (3TC, EPIVIR); abacavir (1592U89, ZIAGEN®) (see W096/30025); adanfodi dipivoxil [double (POM)) -PMEA, PREVON®]; lobucavir (BMS-180194) (see EP-0358154 and EP-0736533), reverse transcriptase inhibitors (in the racemic mixture of BCH-10618 and BCH-10619) Form); emitricitabine [(-)-FTC] (see U.S. Patent No. 5,814,639); PL-D4C and designated ◎ PL-2',3'-dideoxy-5-fluoro-cell (-)-PD-2,6-diamino-indoledioxolane (DAPD) (see EP 0656778); and adenosine (FddA, 9-(2,3-) Dideoxy-2-fluoro-β-D-threofuranosyl) adenine). The term "non-nucleoside reverse transcriptase inhibitor" ("NNRTI") as used herein means a non-nucleoside material that inhibits the activity of HI V-1 reverse transcriptase. · Suitable NNRTIs include, but are not limited to, nevirapine (nevirapineXBI-RG-SW, VIRAMUNE®); delaviradine (BHAP, U-90152, RESCRIPTOR®); efavirenz (DMP-266) , 〇SUSTIVA®) (see W094/03440); PNU-142721 (furopyridine-thio-pyrimidine); AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl) carbonate )-thio-4-isopropyl-1-(4-«pyridyl)indolyl-1H-imidazol-2-ylmethyl ester (see WO 96/10019); MKC-442 (l-(ethoxylated) 5-(1-methylethyl)-6-(phenylmethyl)-2,4(1Η,3Η)-pyrimidinedione)d; and (+)-carradine A ((+)-calanolide A) (NSC-675451) and B, coumarin derivatives (see U.S. Patent No. 5,489,697). 139805.doc -24· 200948363 The term "protease inhibitor" ("pi") as used herein means HIV-1 protease (a viral polymeric protein precursor (eg, viral GAG and GAG Pol polymer) Protein cleavage is an inhibitor of the enzymes required for the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds with peptidomimetic structures, high molecular weight (7600 Daltons), and substantial peptide characteristics, such as CRIXI VAN® and non-peptide protease inhibitors such as VIRACEPT®. Suitable PIs include, but are not limited to, PrezistaTM, saquinavir (Ro 3 1-8959, INVIRASE®, FORTOUASE®); Ritonavir (ABT-538, NORVIR®); Indinavir (MK-639, CRIXIVAN®); nelfnavir (AG-1343, VIRACEPT®); amprenavir (141W94, AGENERASE®); rasinavir (lasinavir) (BMS-234475, CGP-61755); DMP-450 (cyclic urea); BMS-2322623 (azapeptide); ABT-378; and AG-1549 (orally active imidazolidinyl phthalate, Shionogi # S-1153) 〇 Other antiretroviral agents include, but are not limited to, hydroxyurea, ribavirin, IL-2, IL-12, enfuvirtide (FUZEON®), and Yissum Program No. 11607 . The term "antiretroviral agent for the treatment of HIV" as used herein means that it is found to be useful for the treatment of HIV-1 infection, either alone or as a combination of multiple drug combinations (eg, HAART triple and quadruple combination therapy). Any antiretroviral agent. Typical suitable therapies include, but are not limited to, multi-drug combination therapies such as (1) at least three antiretroviral agents selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two selected from 139805.doc -25- 200948363 NNRTI and PI antiretroviral agents. Typical suitable HAART-multidrug combination therapies include: (a) triple combination therapy, such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapy, such as two NRTIs , a PI and a second PI or an NNRTI. In the treatment of patients who have not been treated, it is preferred to start treatment of HIV with triple combination therapy; unless there is tolerance to PI, it is preferred to use two NRTIs and one PI. Drug compliance is required. CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. If the viral load reaches plateau, a fourth drug, such as a PI or an NNRTI, can be added. The following is a summary of typical antiretroviral multi-drug combination therapies: Antiretroviral multi-drug combination therapy A. Triple combination therapy 1. Two NRUsk species PI20 2. Two NRTIsk species NNRTI3 B. Quadruple combination therapy 4

1. Two NRTIs + - PI + second PI or one NNRTI C. Substitute 5 1. Two NRTI1 2. NRTI5 + - PI2 3. Two PIs6+ - NRTI7 or NNRTI3 4. A PI2 + - NRTI7+ - NNRTI3 footnotes: \ One of the following: zidovudine + lamivudine; zidovudine + 139805.doc -26· 200948363 didanosine; stavudine + pull Mifudine; stavudine + didanosine; zidovudine + zalcitabine 2 · indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules. 3. Nevirapine or delavirdine. 4. See A-Μ. Vandamne et al. Antiretroviral Chemistry &

Chemotherapy 9:187 is on pages 193-197. 5. Alternatives are for patients who are unable to take the recommended regimen due to compliance issues or toxicity and who are used to fail or relapse on the recommended regimen. The combination of two nucleosides can cause HIV resistance and clinical failure in many patients. 6. Most data were obtained with saquinavir and ritonavir (400 mg BID each). 7. Zidovudine, stavudine or didanosine. Suitable anti-drugs are also described in "Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 - infected adults and adolescents j Department of Health and Human Service, January 29, 2008; 1-128 Retroviral therapy, which is incorporated herein by reference. It can be administered in combination with Compound I or a pharmaceutically acceptable salt thereof for the treatment of rheumatoid arthritis, transplantation and graft versus host disease. The agents known to be inflammatory bowel disease and multiple sclerosis are as follows: Solid organ transplant rejection and graft versus host disease: immunosuppressive agents, 139805.doc -27- 200948363 Such as cyclosporine and interleukin-l 〇 (IL-10), tacrolimus, anti-lymphocyte globulin, OKT-3 antibody and steroid; inflammatory bowel disease: IL-10 (see US Patent No. 5,368,854), steroids and sulphate Azulfidine; rheumatoid arthritis: amidoxime, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; multiple Sclerosis: interferon beta, interferon alpha and steroids. In addition to the above, a therapeutically effective amount of pegylated interferon-alpha can be combined with a therapeutically effective amount of Compound I or a compound thereof sufficient to reduce the plasma level of HIV-1-RNA Further, the present invention provides a method of treating HIV infection comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of DP- 178 polypeptide or a pharmaceutically acceptable derivative thereof. An additional combination suitable for use in the method of the invention is described in US 6,391,865 ' US 6,689,765 ' US 2004/0067691 ' US 2006/0105964, US 6,635,646 and US 2005/00653 19 Therapies, the contents of which are incorporated herein by reference. Pharmaceutical Compositions Compound I may exist in different isomeric forms (eg, enantiomers, diastereomers, stagomeres and Rotamers. The present invention encompasses lozenges which may contain any such isomers in pure form and in a mixture (including racemic mixtures). Compound I or its pharmaceutically acceptable in unit dosages The amount of salt can by from about 1 billion mg to about 1 50 mg, preferably from about 0 1 mg to about 139805.doc -28 · 200948363 30 mg varied or adjusted according to the particular application. In certain preferred embodiments, the amount of the compound or pharmaceutically acceptable salt is equivalent to 24.6 mg of the free base of Compound I. The amount of the compound in a unit dose or a pharmaceutically acceptable salt thereof is preferably 3 〇 mg for the treatment of HIV infection, and particularly preferably wherein the pharmaceutically acceptable salt of the compound is butylene. Acid salt. The amount of the dose used will vary depending on the needs of the patient and the severity of the condition being treated. Determining the appropriate dosing regimen for a particular situation is within the skill of the art. For the sake of convenience, it may be divided and administered daily during the day. The dosage and frequency of Compound I or its pharmaceutically acceptable salt will be considered according to the attending physician, such as the age, condition and size of the patient. The judgment of the factors that determine the severity of the symptoms is adjusted. A typical recommended dosage regimen for oral administration can range from about 20 mg/day to about 1 mg/day, preferably from 2 mg/day to 60 mg/day, more preferably about 3 mg. /day. In a preferred embodiment, the daily dose of the maleic acid salt of Compound I is 3 mg/day, and 4 is effective at 24.6 mg of the free base (Compound), and is administered in a single dose. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered to an HIV positive patient in an optimized background regimen containing ΡΙ/r. More preferably, Compound I or a pharmaceutically acceptable salt thereof is administered to an HIV positive patient at a dose of 30 mg/day in an optimal background treatment with pi/r. Dosage and dosing regimen for NRTI, NNRTI, sputum and other agents will be prescribed by the attending physician in view of the package insert or as specified in the protocol that takes into account the patient's age, gender and condition, and the severity of HIV-1 infection. And the drug is determined by the 139805.doc -29- 200948363 case. Although the present invention has been described in connection with the specific embodiments set forth above, many alternatives, modifications and variations are apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of the invention. EXAMPLES Exemplary tablet formulations of the maleate salt of Compound I are detailed in Tables 1.1 and 1.2. Various grinding/deblocking conditions (which represent the worst case drug substance in terms of particle size distribution (maximum proportion of fines and therefore large specific surface area)) are used by using micron-sized drug substances (prepared from batch material A). To determine the stability of the high shear wet granulation process. For the processability and the absence of adhesion to the surface of the punch, the seventh batch of drugs (Table 1.2) made with micron-sized drug substance B under 10% drug load was expressed as a "standard" drug substance (batch). Other batches made by item number A) are similar. The 8th and 9th batches of the drug under the 15% drug load alone showed the formation of a microfilm on the surface of the tool. Table 1.1 - Composition of exemplary bond formulations Drug lot number 1 2 3 4 5 6 Drug substance number AAAAAA (mg/key) Compound I maleate 10 10 10 10 10 10 (mg/key) Granular Excipient Microcrystalline Cellulose (MCC) 10 0 0 0 0 0 Lactose monohydrate (very fine) 51 56 54 58 56.5 55.5 Croscarmellose sodium (NaCC) 2 2 3 1 2 2 Povidone 4 4 4 4 4 4 (mg/key) Extragranular Excipient Microcrystalline Cellulose (MCC) 20 25 25 25 25 25 Croscarmellose Sodium (NaCC) 2 2 3 1 2 2 Magnesium Stearate (MS) 1 1 1 1 0.5 1.5 Total bond weight (mg) 100 100 100 100 100 100 139805.doc •30· 200948363 [Ingredients for the formulation of the lozenge formulation Lot number 7 8 9 10 11 Drug substance number BAAAA (mg/supplier) Compound I of cis-butenylene 10 15 15 20 20 (mg/key) Granular excipients Microcrystalline cellulose ~~-_ ' 0 0 0 5 0 Lactose early hydrate ( Very fine 1 56 50.5 50.5 30.5 49.5 Croscarmellose sodium 2 2 2 2 2 Povidone 4 4 4 4 4.5 (mg/bond) Extragranular excipients Microcrystalline cellulose 25 25 25 35 20 Cross-linked carboxy Fiber Sodium 2 2 2 2 2 Magnesium stearate 1 1.5 1.5 1.5 2 Total lozenge weight (mg) 100 100 100 100 100 Additional exemplary lozenge formulations are detailed in Table 2, wherein various excipient ranges are examined. In particular, the range and excipients examined were as follows: 1.5% and 2.5% w/w magnesium stearate, 3% and 5% w/w povidone and 2% and 6% w/w cross-linking Carboxymethylcellulose sodium. Micron sized drug substance (Cat. No. c) was used to show the stability of the formulation and method under the worst case of particle size distribution (q9 〇 % < 3 μm) at 20 〇 / drug load The next 18th batch of the drug showed the formation of a microfilm on the surface of the tool. In addition, no filming or adhesion was observed in any of the other exemplary formulations described in Table 2. Table 2 - Excipients Illustrative Formulations for Ranged Routine Compositions Characterized Excipients Magnesium Stearate Cross-Cellulose Sodium Sodium Glyceride Drug Batch No. 12 13 14 15 16 17 18 1 Stock Material No. CCCAAAA (mg/ Lozenges) cis-succinic acid salt of compound I 30 30 30 20 20 20 20 (mg/supplier) granular excipient microcrystalline cellulose 7 .5 7.5 7.5 5 5 5 5 Lactose monohydrate (very fine) 60 60.75 59.25 42 38 41 39 Croscarmellose sodium 3 3 3 1 3 2 2 Povidone 6 6 6 4 4 3 5 (mg/ingot Extragranular excipients Microcrystalline cellulose 37.5 37.5 37.5 25 25 25 25 Cross-linked carboxymethyl cellulose sodium 3 3 3 1 3 2 2 Magnesium stearate 3 2.25 3.75 2 2 2 2 Total lozenge weight (mg) 150 150 150 100 100 100 100 139805.doc -31 · 200948363 Clinical Study No. 1 Clinical Study Interviews (1) Evaluation of Vickerrow (specifically, compound I maleate) as an HIV-infected individual Safety and tolerability of oral administration of 1 〇 mg BID, 25 mg BID, 50 mg BID at 14 days. (Π) Determination of the multi-dose pharmacokinetics and viral pharmacodynamics of vikvero in individuals infected with HIV. This method is a randomized, third-party uninformed (in the dose range), placebo-controlled, multi-dose study in which 49 individuals infected with HIV-1 were assigned to use Vikweero 1〇 Mg BID (- twice daily), 25 mg BID or 50 mg BID or in a treatment with a matching placebo. After the screening phase (days-21 to -3) and baseline (days _2 to -1), eligible individuals are sequentially registered in three groups. Individuals in each cohort were randomly assigned to the Vicvaro group or placebo group at a ratio of 3:1, and the study drug (BID) was administered for 14 days, followed by another 14 days. The next higher dose is administered until the safety and tolerability of the aforementioned doses have been established, not less than 7 days between groups. Individuals were limited to study centers from day -2 to day 7 and day 12 to day 14 for assessment of safety, pharmacokinetics, and pharmacodynamics. The clinic will be pre-arranged on the 9th, 11th, 15th, 16th, 17th, 21st, 25th and 28th days. Blood samples of vikviro pharmacokinetics were taken just before the AM dose on Days 1 and 14, and up to 24 hours later. The Trough sample was obtained just before the pM dose on day 12 and before the AM and PM dose on day 13. Further, samples were taken on the 16th day, the 1st γ day, and the 21st day. Use the COBAS AMPLICORtm HIV] test, vl 5 (R〇che 139805.doc · 32· 200948363 Diagnostic) (automatic PCR amplification and detection with the COBAS AMPLICORTM analyzer) to evaluate Day -1 to Day 7, Viral pharmacodynamics of plasma HIV-1 RNA screened on day 9 and day 11, day π to day 17, and day 21, day 25 and day 28. Fluorescent activated cells (FACS) were panned under screening and on days -1, 2, 7, 14 and 28 for assessment of total lymphocyte count, presence of lymphocyte markers CD3 and CD3/CD4, and The presence of CD3/CD4 and CD3/CD8 related CCR5 and CXCR4 receptor densities. YiroLogic, Inc. (now Monogram Biosciences, Inc.) used PhenoSenseTM HIV test analysis IC50/IC95 to determine phenotypic susceptibility of HIV-1 isolates. ViroLogic also uses the PhenoSense HIV Entry Tropism to determine the co-receptor tropism (ie, the R5/X4 viral phenotype), which is screened and tested on days -2, 7, 14, and 28. The use of chemotherapeutic receptors (CXCR4 and/or CCR5) is performed. Physical examinations, vital signs, and clinical laboratory assessments were performed at screening and at predetermined times during the study period. Multiple time-matched 12-lead electrocardiograms (ECG) were performed at baseline (Day-1) and on Days 1, 7 and 14 and were interpreted by unsuspecting third-party examiners; A single ECG was performed on days 3, 5, 9, 11, 13 and 28. Continuous monitoring of adverse reactions (AE) in individuals.鏔#杀吞.· Registered 49 individuals; treated 48 individuals; 47 individuals completed the study. The breakdown of the treatment group (Breakdown) was as follows: placebo, I3 individuals; Vickerrow 10 mg BID, 12 individuals; Vickerrow 25 mg BID, 13 individuals; and Vickerrow 50 mg BID , 11 individuals. 139S05.doc -33- 200948363 This includes 4 (four): adult males and females, aged 18 to 55 years, infected with pure CCR5_tropical virus, but have not received antiretroviral treatment within 8 weeks prior to enrollment (or No other drugs were received within 2 weeks prior to registration; and had a CD4+ cell count of 2200; HIV viral load was between 5, 〇〇〇 and 200,000 copies/ml; and body mass index (bmi) was between ^ and 29 Those are qualified for research considerations. To be suitable for this study, based on medical history, including history of CNS (ie, no prior episodes or head trauma), physical examination; ECG; and routine laboratory tests (blood chemistry, hematology, and urinalysis), individuals must additionally In good health.涔弑产#, 漱#, 痹Naphthalene 4': vikvero (specifically, the maleic acid salt of Compound I). • Group 1: 1. 10 mg oral (BID) capsules on day 1 to day 13 and on day 14. • Group 2: 1. 25 mg oral (BID) capsules on day 1 to day 13 and on day 14. • Group 3. 2. 2. 25 mg oral (BID) capsules on day 1 to day 13 and on day 14. Bath # # .读#臂··All individuals received their randomized treatment for 14 days and a 14-day follow-up period after the last dose. ###法,身/f,授##4···Placebo matches Vicvalo. • Group 1: 1. 10 mg oral (BID) capsules on day 1 to day 13 and on day 4 of AM. • Group 2: 1· 25 mg oral (BID) capsules on day 1 to day 13 and on day 14. 139805.doc -34- 200948363 • Group 3: 2. AM 25 mg oral (BID) capsules on Days 1 to 13 and on Day 14. #勿越力荸诤 From: The plasma Vickellow concentration data was used to evaluate the following pharmacokinetic parameters on days 1 and 14: AUC (0-12 hr), Cmax and Tmax. The pharmacokinetic parameters evaluated only for Day 14 were: , CL/F, Vd/F and R. The lowest (Cmin) sample from day 12 to day 14 was used to evaluate the steady state conditions of vicvello.痹尨荸诤/Pharmacodynamic variables include: HIV-1 RNA viral load; ® FACS analysis of lymphocyte markers; R5/X4 viral phenotype; susceptibility analysis. Safety is nothing to you. · Throughout the study, physical examinations, multiple time-matched ECGs, vital signs assessments, and clinical laboratory tests were performed, and adverse events were recorded.亲妒才法越力#: The repeated-measures analysis of variance (ANOVA) model for extracting individuals, days, and doses as a classification factor is used for log-transformed Cmax and AUC values ❿. Dose linear trends were studied and a comparison of AUC (0-12 hr) on day 1 versus AUC (0-12 hr) on day 14 was made. The dose normalized AUC (0-12 hr) and Cmax values for day 14 were analyzed by a one-way ANOVA model. To assess steady state, individuals and (continuous) time were used as factors, and ANOVA was performed on Cmin values on days 12, 13, and 14. .Professional method -#Efficacy.·List and summarize pharmacodynamic parameters. The treatment group was at baseline 1 (^10 111 ¥-111^8 and the viral load was listed from the baseline at each time point (except for the parameters specified in the protocol) including the mean, 139805.doc -35- 200948363 Descriptive statistics of values and standard deviations. 截#才法-安全崔.· List all adverse events of the treatment group and list the information. The list of adverse events includes all treatment of sudden adverse events, by severity and treatment The relationship is further categorized. Clinically significant changes from baseline in physical examination are recorded as adverse events. The results of laboratory safety tests and vital sign measurements from all individuals are listed and reviewed. For ECG parameters , summarizing the mean/median change from baseline in the treatment group. 乂口巍学: In this study, a total of 49 individuals infected between 25π” and between the ages of 25 and 53 years (40 males were enrolled; 9 women). Overall, 5,43 individuals were Caucasian (caucasian), 3 individuals were black and 3 individuals were Hispanic. The median body mass index (BMI) was 23.40 (range 16.6-33.2) ).##昜Mechanics. The average pharmacokinetic parameters of vikvero are summarized in the following Table 3. Vickero is rapidly absorbed, and the median peak plasma concentration is observed after administration (d(2) 丨 to 1.50 hours. Inter-individual variability is low to moderate; CV is in the range of 19% to 35°/ for Cmax and 14% to 43% for 811(:(0-12 111:) A linear increase in doses of Cmax and AUC (0-12 hr) was observed when the dose was increased from 1〇〇1§ to 50 mg. The long-term half-life in the range of 28.1 to 32.8 hours was observed on day 14. A steady-state Vickellow violent approach was achieved on day 14 of each dose twice. 139805.doc -36- 200948363 Table 3 - Oral administration of Vik Veero (BID) to HIV-infected volunteers Mean pharmacokinetic parameters of post-Vickevir: AUC (0-12 hr), Cmax and Tmax on day 14. Dose a AUC (0-12 hr) Cmax Tmax (mgBIDb) (ng-hr/ml) (ng/ml) (hr) Mean CV (%) Mean CV (%) Median range 10 (n = ll) 424 34 65.1 32 1 0.5-2 25 (n = 12) 1060 27 149 21 1.5 1- 2 50(n=ll) 2290 43 342 35 1.5 0.5-1.5 a : with maleic acid salt Wick Rivero given dose .i〇 mg, 25 mg and 50 mg of Compound I maleate equivalent to doses of 8.2 mg, 20.5 mg and 41.1 mg of the free base (compound I). b: AM dose administered between 8 AM and 9 AM: PM dose was administered approximately 12 hr after AM dose. #放学, on the 14th day of treatment with vicvello, for all three dose groups, the median change in HIV-1 RNA from baseline was in the range of -0.96 l〇gl〇 to -1.47 loglO, Significantly a significant reduction in HIV-1 RNA was observed in the 25 mg and 50' mg dose groups compared to the 1 mg group. The median value of inhibition of the virus treated with Vicker-Verot was in the range of 1.10 log 10 to 1.74 l〇gl〇. Safety /4 ·· No deaths were reported during the study period. During the study period, 69% of Q individuals reported at least 1 treatment of sudden AE: 62% of individuals receiving placebo and 72% of individuals receiving vicveiroi. There was no dose-related increase in the number of AEs reported by Vicvero. Big. The most commonly reported AEs for vikvero are headache (28%), abdominal pain (14%), ° nausea (14%), and pharyngitis (11%). In these 4 AEs, only headaches (8%, 1 individual) were reported for placebo. Two individuals reported treatment of a sudden severe adverse event (SAE): one with influenza with three related SAEs and the other with stage II syphilis, which occurred 10 days after the end of treatment. In the liver function test, a slight increase in reversibility was observed in 4 individuals treated with veprovir. During the treatment period 139805.doc -37· 200948363, an individual treated with vicvello (50 mg BID) had an isolated QTcF interval above the normal range. Conclusions: In these HIV-infected individuals, the doses of Vickevir for 1〇, 25, and 50 mg BID were adequately tolerated. Most of the £8 is mild to moderate' and there appears to be no dose correlation. • Vickerel was rapidly absorbed and showed dose linear pharmacokinetics with low inter-individual variability and long-term half-life in the dose range studied (10 mg, 25 mg A5 〇 mg BID). • Based on changes in HRM RNA from baseline, effective viral suppression was observed in all three Vickivir-administered groups. After administration, the 50 mg/day and 1 mg/day dose groups all had a mean/median decrease in viral load > 15 log 10. Clinical Study No. 2 swallowed flag. (1) Determination of multi-dose pharmacokinetics of veprovir administered with low-dose ritonavir in healthy volunteers when administered with low-dose ritonavir £ Sex and tolerance. I will catch the low 剜 丨丨杈 4 丨丨杈. (Π) Determination in health volunteering

Patients with optimal background treatment with ΡΙ/r.才法·*This is a randomization (for the first 2 groups)

139805.doc -38- 200948363 A total of 4 8 individuals (12 individuals/group) were registered in 4 groups. Volunteers were screened within 3 weeks of dosing and qualified individuals were restricted to the study center approximately hr prior to the start of dosing (day -2 day). Randomize the first 24 registered individuals to the 20 mg QD (once a day) (group 1) or 3 〇 mg QD (group 2) with ritonavir (丨〇〇瓜吕qd) Vik Veero (specifically, the compound of the maleate) dose. In the morning of the first day, he voted with Vick Vero and on the morning of the same day, he voted for Ritona. Individuals were left in the study center for safety and pharmacokinetic assessment until all 18th day procedures were completed and returned to the clinic for visits on Days 19-21. After reviewing the safety and pharmacokinetic results from the lower dose levels, 50 mg QD & 1 mg mg QD were selected as the doses of Groups 3 and 4, respectively. Blood samples for determining the concentration of vickeric were obtained on day 14 before administration and at the time after administration of at most 24 & 24 hours; the lowest samples were also collected on days 12 and 13. . Additional blood samples of Vickellow were collected on day i5_2i (i.e., 24 & 168 (four) after the last dose of Vickerrow. Obtained for determination of Lito before dosing on day 13-15 Blood samples of Nawei concentration. Blood samples for possible pharmacogenetic analysis were collected from all individuals on day _2. Safety assessment included physical examination, life at _ selected and scheduled for the study period Sign assessment, electrocardiogram (ECG), and clinical laboratory testing. ECG assessment includes matching brains at multiple times on day 1 and day. Continuous observations and inquiries about adverse events (AEs) may occur throughout the study Individuals. 5 Pregnancy age 18 to 55 years old, with a body between 19 and 32 139805.doc -39- 200948363 Mass male heart (BMI) adult male and female individuals are eligible for study considerations. Suitable for this study, based on medical history, including complete cNS history (to rule out pre-existing conditions and/or head trauma); electroencephalogram (EEG); physical examination, ECG, and routine laboratory testing (blood chemistry, blood) Learning and urine ) 'Individuals must be in good health. Source 弑 # #, 漱 #, 痹 痹 4, .. with ritonavir 1 〇〇 mg capsule (Norvir®) - oral administration to Vicvero (specific In other words, the compound of maleate) 1 〇mg tablets and / or 丨 5 mg tablets, as follows: • Dance is 7 .. Vickero 20 mg (2xl0 mg: agent) qd duration 14 days + ritonavir 100 mg QD lasted 20 days. • Dance 2 2. Vickero 30 mg (2xl5 mg lozenge) QD lasted 14 days + ritonavir 100 mg QD lasted 20 days. · Gold 3 · Vikwello 50 mg (5xl0 mg lozenges) QD lasts 14 days + ritonavir 100 mg QD lasts 20 days. • Net. Syria 4 Vik Veero 1〇〇mg (6xl5 mg ingots Agent + ixi 〇 邑 ) ) ) ) ) Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Simultaneous administration. After reviewing the safety and pharmacokinetic results from the previous lower dose levels, the Vickerschild doses of groups 3 and 4 were determined, and groups 3 and 4 were administered sequentially. .. after completing groups 1 and 2 and then after completing each After the group was continued, 'Vickellow safety measurement and pharmacokinetic parameters were analyzed. 痹#乔力学.·Measured for Vickerrow after multiple doses (Day 14) 139805.doc •40- 200948363 The following pharmacokinetic parameters: maximum observed plasma concentration (Cmax), minimum plasma concentration (Cmin) under pre-dose, time of Craax (Tmax), and area under 血浆 to 24 hours under the plasma concentration-time curve (AUC) [〇-24 hr]). In addition, apparent systemic clearance (CL/F), apparent volume of distribution (Vd/F), and terminal half-life 01⁄2 were also calculated when data were allowed. The steady state sample of Vickerrow was evaluated using the lowest concentration sample obtained on days 12 to 15. The concentration of ritonavir was determined for samples taken from day i3 to day 15. Bud Quanxuan. · Perform physical examination, ECG and clinical laboratory tests; monitor ❿ vital signs; and record AE. The ECG assessment includes ECGs that match at multiple times on Days _ and Day 14. #身费力#之旄#才法.. The main pharmacokinetic parameters of Vickellow are AUC and Cmax. Based on the logarithmic transformation AUC and Cmax, each group is provided with a point evaluation along with 90% CI. The steady state was characterized for each dose using the lowest concentration from day 12 to day 15. Pharmacokinetic parameter analysis was performed after completion of groups 1 and 2 and then after completion of each subsequent group. Provides generalized statistics (eg, 'average and standard deviation') for Vickero's pharmacokinetic parameters and concentration data at each Q-sample time. Safety is not a cure. All AEs reported during the study are listed by the individual and the body system. The AE list includes all treatments for sudden ae (teae) and treatment-related TEAE, which are classified by body system and dose level groups. Data from hematology and blood chemistry tests, vital signs assessment, and ECG are listed and reviewed for each individual, and clinically significant findings are recorded as AEs. Mark laboratory values outside the laboratory reference range. The results of the physical examination are reviewed and the clinically significant changes from the screening are recorded as ae. 139805.doc 41 - 200948363 Descriptive statistics are used to summarize ECG parameters as well as safety laboratory variables and vital signs.乂σ . 縿 縿 and 差. 缓# levy / a total of 48 (31 male and female) age between 18 and 54 years (the average age range in the group: 37.7-41.4 years old) health Individuals are randomized to treatment. Most of the individuals in each group are Caucasian: in the range of 67% to 83% in the group. The treatment group is similar in terms of demographic characteristics. ##佥力学.· In Table 4, the summary statistics (mean and %CV) of the pharmacokinetic parameters of veprovir on day 14 were provided for each treatment group. Table 4 - Average (% CV) dimension on day 14 after 20 days of oral administration of 20 mg, 30 mg, 50 mg or 100 mg of veprovir and mg of ritonavir in healthy individuals Kevero pharmacokinetic parameters dose group a Cmax (ng/mL) Tmax (hr) Cmin (mg/mL) AUC (0-24hr) (ng hr/mL) CL/F(L/hr) 20 mg (n =12) 252(24) 2 (1-5) 130(21) 3760(18) 4.53 (21) 30 mg (n=12) 372 (15) 2 (1-3) 213 (22) 6210(18) 4.08(18) 50 mg (n=12) 796(19) 2 (1-4) 456(31) 13100(21) 3.27 (23) 100 mg (n=12) 1380(16) i (1-2) 786(18) 21800(17) 3.87(18) a : The Vickera dose is represented by maleic acid salt. The doses of 20 mg, 30 mg, 50 mg, and 100 mg of Compound I maleic acid were equivalent to 16.4 mg, 24.6 mg, 41.1 mg, and 82.1 mg of free test (Compound 1), respectively, during the study period. A total of 16 individuals (33%) reported at least 1 TEAE: 6 (50%) systems were administered with Vickeroo 20 mg + ritonavir 100 mg (Group 1); 5 (42%) The system was administered with Vickersal 30 mg + ritonavir 1 mg (group 2); 1 (8%) system was administered with vikviro 50 mg + ritonavir 1 〇 〇mg (group 3); and 4 (33%) individuals 139805.doc • 42- 200948363 administered with vewrovir 100 mg + ritonavir 100 mg (group 4). There is no apparent dose-related trend in TEAE.

Gastrointestinal (GI) TEAE is the most common event, with 5 (42%) individuals, 4 (33%) individuals, 1 (8%) individuals, and 1 (8%) reported in groups 1-4, respectively. individual. In GI TEAE, diarrhea and constipation are most often reported. Although the investigators believe that most TEAEs may be associated with study treatment, it is believed that all TEAEs reported during the study are mild in severity and that no individual needs medication to treat TEAE. There was no severe AE (SAE) and no individual withdrew from treatment due to TEAE. No clinically significant changes were reported in blood chemistry or hematology parameters, vital signs or ECG results. The results of multiple time-matched ECGs at baseline (Day-1) and on Day 14 indicate that no individuals had a QTc interval increase of 230 milliseconds (Fridericia Correction (QTcF Interval) from time-matched baseline). All values of the QTcF interval measured on day 14 were maintained within a gender-specific normal range, i.e., $430 milliseconds for male individuals and $45 milliseconds for female individuals. Conclusions: • Cmax, Cmin, and AUC (0-24 hr) of Vickellow are dosed (20 mg, 30 mg, 50 mg, and 100 mg) once daily with 100 mg of ritonavir. Increase and increase. A similar CL/F value indicates no change in elimination between doses. A steady state was reached on the 14th day. • Together with ritonavir (100 mg QD) - a dose of 20 mg, 30 mg, 50 mg, and 100 mg per dose of Vikwello administered to healthy individuals for 2 weeks is safe and well tolerated of. There is no apparent dose-related trend in the appearance of TEAEs 139805.doc -43- 200948363. No clinically significant changes were reported in blood chemistry or ash fluid parameters, vital signs or ECG results. Clinical study No. 3 is exhaustive. (1) To evaluate the effect of protease inhibitors (such as darunavir) on the pharmacokinetics of vicproro in the presence of ritonavir; and (9) to assess the accompanying ΡΙ/r (ground) The safety and tolerability of rivalvir in rivalvir and ritonavir. This method is an open-label, fixed-sequence, two-stage, multi-drug interaction study conducted in 12 healthy adult individuals at a single research center. The study was conducted in accordance with Good Clinical Practice (GCP). Volunteers were screened within 3 weeks of dosing and were started at 12 hr (days) prior to dosing (for baseline assessment to reconfirm eligibility) to limit eligible individuals to the study center. Individuals on day 1 8 AM received its first dose of study drug. For the first 14 days of treatment (Day -14 days), the individual received Vickerrow in combination with ritonavir (100 mg BID) (specifically, compound 丨Maleate is 30 mg (QAM) once a day in the morning. For the next 14 days (Day 15 28), darinavir (600 mg BID) is added to the existing treatment. All study drugs All were taken with food. Individuals were left in the study center until day 29 for safety and pharmacokinetic assessment, and returned on day 33 for follow-up visits. On days 14 and 28, before dosing from dosing to giving A continuous sample of the pharmacokinetic analysis of Vikwello was obtained 24 weeks after the drug; the lowest sample was also collected on days 12, 13, 26 and 27. On day 14 and 28 Blood samples for analysis of ritonavir were collected before morning administration. Self-sufficient on day 28. A continuous blood sample for the analysis of 139805.doc • 44 - 200948363 % Nafon was obtained from the beginning to 24 hr after administration. Blood samples were also collected from the licensed individuals for possible pharmacogenetic analysis on day-May. The safety assessment includes a physical examination, a vital sign δ flat assessment, an electrocardiogram (ECG), and a clinical laboratory test under screening and at a predetermined time during the study. Adverse events (ΑΕ) may occur throughout the study. Continually observe and ask the individual. More and more. Register 12 individuals and all individuals complete the study. This includes Meng Feng and Ji Yuan. Ages 18 to 55 years old, with between 19 and 32 kg Adult male and female individuals with a body mass index (ΒΜΙ) between /m2 are eligible for study considerations. Suitable for this study, based on medical history, including a complete history of CNS (to exclude pre-existing conditions and/or head trauma) ); physical examination; ECG; and routine laboratory tests (blood chemistry 'hematology and urinalysis') individuals must be in good health. Wide / test #法, body / #, authorization mode.. Vickero ( Specifically, the cis-succinate salt of the compound I) 3 〇 mg tablet qam>< 28 days (day 1 to day 28), ritonavir (Norvir®) l 〇〇 mg capsule BIDx; 28 days (day 1 to day 28) and darinavir (PrezistaTM) _ called (2><3〇〇mg lozenges) BIDX for 14 days (day 15 to day 28). All medications and food Give it together by mouth. # ##居,#/#,授#旗4' ··维克罗罗 (specifically, compound I cis succinate) 3〇mg lozenge qamx 14 days Tonavi (N〇rvir®) 100 mg capsule BIDxl4 days (No! Days to the 14th day). All medicines are given orally with food. Governance ##·Continue to vote for Vikwello QD and Litonavir BID for 28 days (Day 1 to 28 days), and darinavir b ID for 14 days (Day 15 to 139805.doc -45- 200948363 Day 28). Γ '赛(四)力爹.. After multiple doses, the following pharmacokinetic parameters were measured for Vickerrow and the ground: (5), in the pre-dose (the lowest mound in the underarm (Cmin) , "The time when the maximum value was observed in the day (AUC [0-24 hr] for Vickovo and AUC [0_12 hr] for darunavir). In addition, the apparent systemic clearance was calculated (cl/ f). The plasma concentration of ritonavir (Cp 〇 hr) at time 〇hr was measured on day 14 and day 28. 才莩娜_安全姪. Perform physical examination, ecg and clinical laboratory tests; monitor life Signs; and record AE. • Silk 縿 _ _ Qin #影力学.. Provides summary statistics on concentration data and pharmacokinetic parameters at each sampling time on day 14 and day (mean, standard deviation [ SD] and coefficient of variation [cv]). Use extraction by treatment and -

The single factor variation analysis (AN〇VA) model of the effects of the body was used to statistically analyze the logarithmic transformation data of Vickero AUC, Cmax and Cmin on days 14 and 28. The main concern was the Vickyro Cmax and AUC on Day 28 (Vick Vero + Ritonavir + darunavir) vs. on Day 14 Q (Vick Ronald + Litona) Wei) Vickero's comparison between Cmax and Auc. The logarithmic conversion AUC, Cmax, and Cmin, along with the associated 90% confidence zone (CI), provides relative bioavailability on day 28 relative to day μ. The steady state of plasma vickeric concentration was assessed during the first treatment phase (Vickevir + ritonavir) using the lowest value of the sample on day 12-15, and in the second treatment phase (Vicke Vero) + ritonavir + darunavir) was assessed using the lowest value sampled on days 20-29. 139805.doc -46- 200948363 旄妒法法-安全尨.·List all AEs recorded during the study period. List by treatment and body system/organ class (BSOC) wAE. The individual is listed and 'paragraphs from hematology and blood chemistry tests, vital signs assessment and ECG data' and clinically significant findings are recorded as Ae. Mark laboratory values outside the laboratory reference range. The results of the physical examination are reviewed and clinically significant changes from screening are recorded as AEs.乂 σ cut 5/· and save the stagnation. A total of 12 (6 males and 6 females) of healthy individuals between the ages of 21 and 53 (average 42 3 years old) were enrolled in the study. Ten (83%) of the individuals were Caucasian, and two (17%) individuals were black or African American; all individuals were of Spanish or Latin American ethnicity.戚扁#理学昜力学.·When Vick Vero and ritonavir and darunavir were jointly voted, Vick Vero’s exposure was related to when Vikvero and Litona alone The similar exposures at the time indicated that there was no substantial interaction between vikverovir and darunavir in the ritonavir-containing regimen. For samples collected from day 12 to day 15, the plasma concentrations of vacancies were consistent in the presence of ritonavir. For the test collected from day 26 to day 29, and a, in the presence of p/r (i.e., ritonavir and darunavir), the plasma concentration of vicfuro was consistent. The average treatment rate and 90% CI of Avic (〇_24 hr), Cmax and Cmin of Vickerrow in the presence of ritonavir (with or without darunavir) are presented in Table 5 below: 139805. Doc 47· 200948363 Table 5 - Logistic conversion AUC (0-24 hr), average treatment ratio of Cmax and Crnin, and 90% confidence interval parameters (units) on Day 14 and Day 28 Comparison a Ratio evaluation (%) 90% confidence interval AUC (0-24hr) (ng_hr/mL), n=12 Day 28 / Day 14 93 90-97 Cmax (ng / mL) Day 28 / Day 14 83 79-88 Cmin (ng/mL) Day 28/Day 14 103 99-108 a: On Days 1-14, the individual received Vik Veero (3 〇 mg QAM) in combination with ritonavir (100 mg BID). On days 15-28, the individual received Vikwello (30 mg QAM) in combination with ritonavir (1 mg BID) and darunavir (6 mg BID). The pharmacokinetic parameters of veprovir co-administered with ritonavir in the presence or absence of darunavir are summarized in Table 6 below. Table 6 - Pharmacokinetic Parameters Treatment of Vickerrow on Days 14 and 28 (days) Cmax (ng/mL) Tmax (hr) Cmina (ng/mL) AUC (ng-hr/ml) CL /F (L/hr) Mean CV (%) Mean CV (%) Mean CV (%) Mean CV (%) Mean CV (%) Vick Vero + Ritonavir b (14th) Day), η = 12 381 25 3 2-6 208 22 6290 19 4.08 22 Vickero + ritonavir + darunavir £ (Day 28), η=12 314 20 3 1.5- 6 215 24 5900 21 4.37 23 CL/F = apparent systemic clearance; CV = coefficient of variation. Pressure: Cmin was measured on Ohr (pre-dose) on days 14 and 28. b: On day 1-14, the individual received Vickerrow (30 mg QAM) in combination with ritona, (1 〇〇 mgBn). c: On Days 15-28, the individual received Vickerau (30 mg QAM) in combination with ritonavir (1 mg BID) and darunavir (600 mg BID). Safety 尨. A total of 7 (58%) individuals reported at least one treatment of sudden AE (TEAE) during the study. Three (25%) individuals reported TEAE starting at the same time that the individual received vickeroline and ritonavir alone; 5 (42%) individuals 139,805.doc -48· 200948363 reported one or more in dinadina Wei added to the TEAE that started after the treatment. Among the individual individuals, the only TEAE reported at the time of individual acceptance of vicfuro and ritonavir alone was diarrhea, constipation and headache. TEAE occurring in more than one individual during the study was diarrhea (3 individuals), constipation (2 individuals), and increased alanine transaminase (ALT; 2 individuals). Gastrointestinal disorders are the most common type of TEAE and have been reported in a total of 5 (42%) individuals. in conclusion:

• In the PI/r regimen with darunavir and ritonavir, the pharmacokinetic parameters of vicfuro have not changed substantially. Therefore, it is not necessary to adjust the dose of vicfuro in this regimen. • In healthy adult individuals, Vikwello (30 mg qD) is safe and safe when combined with the ritonanar (100 mg BID) (alone or with darunavir (600 mg BID)) Fully tolerated. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a flow chart of a method for producing an exemplary tablet of a cis-butylate salt of Compound I by a high shear wet granulation process. 139805.doc 49-

Claims (1)

200948363 VII. Application for patent Fan Park · · Seeds of 3 kinds of granules for oral injection, the particles contain Bu [(一), 6_一 methyl-5_°密咬) Several groups M-[4-[2 -Methoxy-1 (RH4-(trifluoromethyl)phenyl]ethyl]-3-(s)-methylpiperidine]_4_methyl-pyridinidine (Compound I) or its medicinal An acceptable salt and a binder, a disintegrant, and a dilution thereof, wherein the compound or a pharmaceutically acceptable salt thereof constitutes 10% by weight to 20% by weight of the tablet. The pharmaceutically acceptable salt of the compound is a maleate at a dose of 30 mg. 3. The lozenge of claim 1, wherein the binder is microcrystalline cellulose, alum, Polyethylene glycol, natural rubber, synthetic rubber, povidone (PVP), pregelatinized starch, Hpc, HpMC, or a combination of two or more thereof. A lozenge, wherein the binder is pvp. 5. The lozenge according to claim 1, wherein the disintegrant is sodium starch glycolate, carboxymethylcellulose or a salt thereof, croscarmellose or a salt thereof, Cross-linked povidone (cr〇spovidone) or Salt, methylcellulose, microcrystalline cellulose, HPC substituted with mono- to hexaalkyl, starch, pregelatinized starch, brown algae, or a combination of two or more thereof. a lozenge wherein the disintegrant is a cross-linked carboxyindole cellulose salt. The lozenge of claim 1 wherein the diluent is lactose, mannitol, xylitol, dextrose, sucrose, sorbus Sugar alcohol, microcrystalline cellulose, starch, anhydrous dibasic calcium phosphate or a combination of two or more thereof. 139805.doc 200948363 8. 9. A tablet as claimed, wherein the diluent is microcrystalline fiber The lozenge of claim i, wherein the diluent is a combination of microcrystalline cellulose and lactose early hydrate. 10·If the lozenge of Qingyou's additionally contains extragranular excipients, the extragranular excipient The agent is lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, anhydrous dibasic calcium phosphate or a combination of two or more thereof. The lozenge 'further additionally comprises an extragranular excipient which is microcrystalline cellulose. For example, the tablet of the 'individuals' additionally comprises an extragranular excipient, which is a transglycolic acid, a methyl cellulose or a salt thereof, a crosslinked: cellulose or a salt thereof, Cross-linked povidone or a salt thereof, methyl cellulose, microcrystalline cellulose, HPC substituted by a sulphur-burning group, a temple powder, a pre-gelatinized lake, a sodium alginate or both or more 13. The tablet of claim 1 further comprising a granule phase agent, the extragranular excipient being a croscarmellose salt. 14· t of the lozenge of claim 1, additionally comprising granules A topical excipient which is magnesium stearate, calcium stearate, zinc stearate, stearin, butadiene sodium lauryl sulfate, or a combination of two or more thereof. A lozenge of claim 1, which additionally comprises an extragranular excipient which is magnesium stearate. 16. A lozenge according to the formula, wherein the compound or a pharmaceutically acceptable salt thereof constitutes 2 parts by weight of the tablet. 7. A lozenge according to claim 1, wherein the granule constitutes from 65% by weight to 139,805.doc 200948363 7 % by weight of the tablet. 18 - The rotatory agent of claim 1 wherein the binder constitutes from 2% by weight to 8% by weight of the bond. 19. A tablet comprising 'dimercapto-5-pyrimidinyl)carbonyl]4[4_[2-methoxy-l(R)-[4-(trifluoromethyl)phenyl]ethyl]_3_ (s)_Methyl_ι_piperidinyl]-4-methyl-piperidine (particles of the compound hydrazine or a pharmaceutically acceptable salt thereof) which is administered to the patient one day with an optimized background treatment containing ΡΙ/r When administered at a dose equivalent to 24.6 mg of the free base of Compound I, an average steady state auc of at least 4968 ng-hr/ml of Compound I is provided; 20. The lozenge of claim 19, which is in the Providing an average steady state Cmax of Compound I of at least 297 ng/mL in the range of up to about 3 hours and at an average Tmax, a tablet containing iota [[4,6-dimethyl-5-) Pyrimidinyl)carbonyl[2-methoxy-l(R)-[4-(trifluoromethyl)phenyl]ethyl]·3_〇methyl-peptidyl]-4-mercapto-piperidine a granule of a compound hydrazine or a pharmaceutically acceptable salt thereof, which is administered to a patient once a day at a dose equivalent to 24.6 mg of Compound I, in an optimized background treatment containing ΡΙ/r, at least The average steady state Cmin of Compound I at 200 ng/mL. 22. As requested in Item 21 A tablet, wherein the pharmaceutically acceptable salt of Compound I is a 30 mg dose of cis-succinic acid salt. 23. The tablet of claim 21 wherein the particle further comprises a binder, a disintegrant and A tablet according to claim i, wherein the granule is prepared by a process comprising the following: 139805.doc 200948363 (a) Dry blending: (i) Compound I or pharmaceutically acceptable thereof And (ii) a disintegrant and a diluent to provide a first dry blending powder; (b) using the granulating solution comprising water and a binder, the first dry blend prepared in the step "&" Dispersing agent is cohesive in a high shear granulator; (c) forming the wet abrasive particles by the wet preparation prepared in the wet milling step rb"; (d) the wet grinding of the drying step rc" The granules form dry granules; and (e) the dry granules of the dry milling step "d". A method of treating HIV infection in a patient with an optimized background treatment comprising ΡΙ/r, comprising administering to the patient in need thereof a therapeutically effective amount of a lozenge according to any one of claims 1, 19 or 21. . A method of treating an inflammatory condition comprising administering to a patient in need thereof a therapeutically effective amount of a lozenge as claimed. 139805.doc -4 -