Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• the present invention relates to high-dosage extended-release formulation of gepirone and methods of treating major depression by administering the same to a subject in need thereof. More specifically, the present invention relates to a high-dosage extended-release tablet form of gepirone. The present invention also relates to a method of treating depression in mammals by administering to a subject in need thereof an effective amount the high- dosage extended-release formulation of gepirone in accordance with the present invention.
• Gepirone also known as 4,4-dimethyl-l-[4-[4-(2-pyrimidinyl)-l-piperazinyl]-butyl]- 2,6-piperidinedione hydrochloride
• 4,4-dimethyl-l-[4-[4-(2-pyrimidinyl)-l-piperazinyl]-butyl]- 2,6-piperidinedione hydrochloride can be obtained by the process described in Example 7 of Temple, US patent 4,423,049, (which is incorporated herein in its entirety by reference) and has the following structure:
• Gepirone and its salts are known to possess antidepressant and anxiolytic properties, presumably by serving as an agonist of the 5-HT 1A receptor. They are typically used to treat depression, dysthymia, impulse disorders, panic attacks and the like. However, in immediate-release formulations, gepirone has a short half-life. The time to maximum drug concentration of gepirone in the bloodstream (T max ) is about 1 hour and its T 5 o (i.e., time until 50% of the drug has been released under controlled in vitro conditions) is about 2.5-3 hours (see U.S. 5,478,572, incorporated herein in its entirety by reference).
• gepirone has been administered in the past in several small dosages--e.g., 5 to 10 mg doses, 2 to 3 times per day.
• this multiple dosing scheme can lead to compliance problems.
• failure to take the second or third dose results in unacceptably low plasma levels of gepirone.
• studies indicate that, for 15 to 20 hours after administration, oral immediate release gepirone formulations can yield significant variations in human plasma concentrations. (For as further discussion see D.S.Robinson et al, Clinical Therapeutics, 1618-1633 (2003)).
• each patient requires a different dosage level to specifically tailor the therapy to that patient's physical make-up, age, and disease complexity. Therefore, even with the low-dosage extended-release form of gepirone disclosed in U.S. Pat. No. 5,478,572, multiple dosing may be required (i.e., 4 tablets of a 20- mg dosage as opposed to a single high dosage tablet), which is inconvenient and expensive. And, as such, there remains a critical need for high-dosage extended-release form of gepirone having a dissolution profile analogous to the low-dosage extended-release form of gepirone disclosed in U.S. Pat. No. 5,478,572, while maintaining the same relative bioequivalence.
• gepirone or bioactive metabolite thereof, as a free base or a pharmaceutically acceptable salt thereof;
• (3) further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of colorant, microcrystalline cellulose, colloidal silica and magnesium stearate; (2) is hydroxypropylmethylcellulose having a viscosity of from about 15,000 cps to about 100,000 cps; and (a) ranges from about 15.5 to about 18.7 wt%.
• Another object of the present invention is to provide a composition containing:
• the tablet has an ovoid-rectangular shape with either biconvex or flat faces.
• the tablet has an overall dimension of 0.400 ⁇ 0.05 inches by 0.325 ⁇ 0.05 inches with a thickness of 0.240 + 0.025 inches (biconvex faces) or a thickness of 0.195 ⁇ 0.025 inches (flat faces).
• the total weight of said tablet preferably ranges from 350 to 450 mg.
• object of the present invention is to provide a method of ameliorating depression, anxiety, or psychological disorders (in particular depression) by administering to a patient (in particular a human) in need thereof an effective amount of the compositions or tablet form of the compositions in accordance with the present invention.
• Another object of the present invention is to provide methods of making the aforementioned tablet forms of the compositions of the present invention.
• Figure 1 shows the comparative dissolution profile of 20 mg and 60 mg tablets described in the Preparation Example under in 0.01 M HCl (see Example 1).
• Figure 2 shows the comparative dissolution profile of 20 mg and 60 mg tablets described in the Preparation Example under in water (see Example 1).
• Figure 3 shows the comparative dissolution profile of 20 mg and 60 mg tablets described in the Preparation Example under in a pH 4.5 media (see Example 1).
• Figure 4 shows the comparative dissolution profile of 20 mg and 60 mg tablets described in the Preparation Example under in a pH 6.8 media (see Example 1). DETAILED DESCRIPTION OF THE INVENTION
• the present invention is based, in part, on the inventor's discovery that a high-dosage extended-release form of gepirone can be obtained wherein the dosage form has a comparable dissolution profile and bioequivalence (for 1-PP, 3'-OH gepirone, and gepirone) to that of the low-dosage extended-release form of gepirone disclosed in U.S. Pat. No. 5,478,572, despite a reduction in the overall ratio between active ingredients and the release- controlling polymer (binder).
• Extended release drug forms offer several advantages over immediate-release systems. Patient compliance is better because the extended release dosage forms need be taken only once in a 24-hour period. Thus, plasma concentration levels do not vary unacceptably ⁇ i.e., give high initial drug levels that are associated with the incidence of unwanted side effects, as well as having rapid drops in drug levels to below therapeutic levels—when the ER dosage forms are administered. In addition, in the case of gepirone, due to the slow time-release 1-PP levels are maintained at a satisfactory level thus avoiding significant complications arising from this metabolite.
• the present invention provides a pharmaceutical composition for making an oral extended release gepirone dosage form comprising:
• gepirone containing, expressed in weight percent:
• gepirone or bioactive metabolite thereof, as a free base or a pharmaceutically acceptable salt thereof, for example a hydrochloride salt,
• the aforementioned embodiment is defined in terms of particular compounds for each component, it is to be understood that within the scope of the present invention these components may be replaced individually or in various combinations as described below.
• the recited weight percentage reflects the total concentration of each component. For example, if there is a mixture of compounds that fall within the scope of a defined component group the recited weight percentage reflects the total for that mixture of compounds.
• component (a) is present in the extended-release oral dosage form in a weight percentage of about 14.0 to about 24.4%, more preferably about 15.5 to about 18.7%. It is particularly preferred that component (a) be gepirone or a pharmaceutically acceptable salt thereof.
• gepirone In vivo, gepirone is metabolized resulting in to major pharmacologically active metabolites: l-(2-pyrimidinyl)piperazine (1-PP) and 3'-OH gepirone (D. S. Robinson et al, Clinical Therapeutics, pp. 1618-1633 (2003)). Two additional metabolites that may also posses bioactivity are also formed in vivo: 5-OH gepirone and 3',5-dihydroxy gepirone.
• 1-PP a common azapirone metabolite
• 1-PP is a presynaptic ⁇ -2-adrenoceptor antagonist and it has been reported that it did not exhibit antidepressant-like characteristics in pre-clinical tests (D. S. Robinson et al, Clinical Therapeutics, pp. 1618-1633 (2003)).
• bioactive metabolites (3'-OH gepirone, in particular) have significant affinity for 5-HT 1A receptors.
• gepirone has been demonstrated to modify 5 -HT neurotransmission in a comparable manner to gepirone even though 3'-OH has been found to exhibit full agonism at post-synaptic receptors in the hippocampus, whereas gepirone is a partial agonist (D. S. Robinson et al, Clinical Therapeutics, pp. 1618-1633 (2003)).
• one or more of the bioactive gepirone metabolites 3'-OH gepirone, 5-OH gepirone, and 3',5-dihydroxy gepirone, or a pharmaceutically acceptable salt thereof, may be used in place of gepirone.
• gepirone or the bioactive gepirone metabolites may be in a hydrate form, an enantiomeric form or mixture, or crystal form.
• the pharmaceutical compounds suitable for administration in the present invention may be hydrochloride salts, but the free bases and other pharmaceutically acceptable salts are also suitable.
• pharmaceutically acceptable salt is well known in the art and the artisan is directed to S. M. Berge, et al. (J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference) for a further description.
• Suitable pharmaceutically acceptable salts for administration in the present invention include acid addition salts.
• the acid addition salt may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, perchloric acid, sulphuric acid, oxalic acid, or malonic acid.
• a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, perchloric acid, sulphuric acid, oxalic acid, or malonic acid.
• a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, perchlor
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, salts of amine groups.
• Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• component (b) is present in the extended-release oral dosage form in a weight percentage of about 70.5 to about 82.1%.
• component (b) is hydroxypropylmethylcellulose having a viscosity of from about 15,000 to about 100,000 cps, which is a release-controlling polymer & binder (a.k.a., sustaining agent).
• Suitable matrixes include hydroxyalkylsubstituted alkylcelluloses having viscosities of about 15,000 cps to about 100,000 cps.
• suitable hydroxymethyl propylcellulose (HPMC) samples include grades Kl 5M and KlOOM (i.e., 15,000 and 100,000 cps, respectively).
• HPMC may be replaced (all or in part) or added to in the present invention, the replacement of some or the entire HPMC matrix may be with dicalcium phosphate or lactose, each of which generally increases dissolution rates.
• the formulation of the present invention may also contain auxiliary binding agents, such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl pyrrolidone.
• suitable fillers or extenders also include starches (e.g., maize-starch), lactose, sorbitol, glycine, sucrose, glucose, mannitol, and silicic acid, sodium citrate and dicalcium phosphate.
• suitable binders may include chitosan, alginates, gelatin, polyvinylpyrrolidinone, sucrose, acacia, and mixtures thereof.
• the ratio of gepirone to binder ranges from 1:3.5 to 1:14.5.
• the binder is hydroxymethyl propylcellulose (HPMC).
• component (c) is present in the extended-release oral dosage form in a weight percentage of 0 to about 1%, preferably 0 to about 0.3%.
• component (c) may be any colorant, it is preferred that the colorant be an iron oxide. In a particularly preferred embodiment the iron oxide is red ferric oxide, yellow ferric oxide, or mixtures thereof.
• Additional exemplary colorants that may be used in place of or in addition to the foregoing include, but are not limited to, FD&C and D&C lakes, titanium dioxide, iron oxides, natural pigments, or dyes approved for ingestion by the U.S. Federal Drug Administration, or combinations thereof.
• component (d) is present in the extended-release oral dosage form in a weight percentage of about 8.0 to about 16.7%.
• component (d) may be any diluent and/or compression aid, it is preferred that the diluent/compression aid be microcrystalline cellulose.
• Additional diluents may include, but are not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,
• the ratio of gepirone to diluent ranges from 1:3 to 2.5:1.
• the diluent is microcrystalline cellulose.
• component (e) is present in the extended-release oral dosage form in a weight percentage of about 0.39 to about 0.47%, preferably about 0.42 to about 0.47%.
• component (e) may be any glidant, it is preferred that the glidant be colloidal silica (colloidal silicon dioxide).
• Additional glidants include, but are not limited to, cornstarch, talc, or stearic acid, or combinations thereof.
• component (f) is present in the extended-release oral dosage form in a weight percentage of about 0.29 to about 1.0%.
• component (f) may be any lubricant, it is preferred that the lubricant be magnesium stearate.
• Additional lubricants may include, but are not limited to cellulose, talc, polyethyleneglycol, silicas, sodium lauryl sulfate, calcium stearate, and mixtures thereof.
• the extended-release oral dosage form may also contain, in addition to components (a) through (f), various additional components.
• components (a) through (f) various additional components.
• the extended-release oral dosage form may include one or more additional pharmaceutically acceptable carriers.
• pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filer, diluent, encapsulating material or formulation auxiliary.
• the extended-release oral dosage form may include may also include one or more releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.
• the flavorant(s), which is used primarily for taste- and/or odor-masking, may be vanillin, sodium citrate, citric acid, mint, orange, lemon oil, or any other pharmaceutically approved flavorant or tastemasking agent, and combinations thereof.
• the present invention contemplates extended-release oral dosage forms that are suitable for orally administration.
• These forms include tablets, capsules, caplets, lozenges, powders, suspensions, syrups and the like are suitable forms.
• the tablet may be mentioned including those having a convex shape, a spherical (i.e., round) shape, or a capsule shape.
• the extended-release oral dosage form of gepirone is a tablet.
• the tablet has oval shape, which enhances their surface area and improves the release of gepirone therefrom. More preferably, the tablet has an ovoid-rectangular shape, which may have either flat or biconvex faces.
• the extended-release oral dosage form of gepirone is a tablet having an ovoid- rectangular shape
• the tablets have an overall dimension of 0.400 ⁇ 0.05 inches by 0.325 ⁇ 0.05 inches with a thickness of 0.240 + 0.025 inches (biconvex faces) or 0.195 ⁇ 0.025 inches (flat faces).
• the overall tablet weight ranges from 350 to 450 mg, preferably from 375 to 425 mg, more preferably from 385 to 410 mg. Further, within the context of the present invention, the tablet weight range of 350 to 450 mg, preferably from 375 to 425 mg, more preferably from 385 to 410 mg correspond to the total weight of the unit dose form.
• compositions i.e., extended-release oral dosage form of gepirone
• the pharmaceutical compositions preferably contain between about 55 to 100 mg (preferably from 60 to 80 mg, more preferably 60 or 80 mg) of the active ingredient per unit dose.
• the tablets may, if desired, be coated using known methods and excipients that may include enteric coating using for example hydroxypropylmethylcellulose phthalate. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
• the contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• buffering agents include polymeric substances and waxes.
• compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• Gepirone can be orally administered in once-a-day extended release dosage forms, which contain gepirone hydrochloride (or a bioactive metabolite thereof), a cellulosic polymer matrix and suitable amounts of pharmaceutical excipients.
• the resultant gepirone formulation yields oral products the take about 19 to about 24 hours to release 90 to 95% of the active agent.
• yet another embodiment of the present invention is a method of treating a patient diagnosed as suffering from major (primary or general) depression, with or without generalized anxiety disorder, comprising administering to said patient an effective amount of the extended-release oral dosage form gepirone as described in the present application.
• the patient in need of treatment is first diagnosed as suffering from a particular depressive condition.
• a particular depressive condition preferably a human, but inclusive of all mammals
• DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Washington, D. C, 2000; Depressive Disorders: 369-428, and Anxiety Disorders: 429-484.
• gepirone extended-release composition and dosage forms of the invention are designed to deliver an effective anti-depressive and/or anxiolytic amount of gepirone or a pharmaceutically acceptable salt thereof to a mammal, preferably a human patient.
• Effective doses refer to an amount of about 0.01 to 40 mg/kg body weight/day are contemplated, preferably 0.05 to 20 mg/kg body weight/day, more preferably 0.1 to 2 mg/kg of body weight/day. For certain central nervous system disorders, 15 to 90 mg/day, preferably 30-60 mg/day, are recommended. See U.S. Pat. No. 4,771,053 and U.S. Pat. No. 5,478,572. Alternatively, the effective dose or delivery system should result in plasma concentrations in the range of about 1 ng/ml to about 20 ng/ml, preferably about 1 ng/ml to about 5 ng/ml.
• the extended-release oral dosage form of gepirone for use in the inventive method contains, expressed in weight percent:
• gepirone or bioactive metabolite thereof, as a free base or a pharmaceutically acceptable salt thereof, for example a hydrochloride salt,
• gepirone in the extended-release oral dosage form of gepirone also embraces the bioactive gepirone metabolites selected from the group consisting of 3'-OH gepirone, 3',5-dihydroxy gepirone, and 5-OH gepirone.
• the method may employ any one of these compounds.
• combinations of these metabolites, or combinations of the metabolites with other active or inert ingredients, are also contemplated.
• the present invention further provides methods for ameliorating depression, anxiety, or psychological disorders in a patient (preferably human, but inclusive of all mammals) in need of such treatment, by administering to the patient an effective amount or dose of gepirone or a bioactive gepirone metabolite such as 3'-OH gepirone, 3',5-dihydroxy gepirone, and 5-OH gepirone.
• a bioactive gepirone metabolite such as 3'-OH gepirone, 3',5-dihydroxy gepirone, and 5-OH gepirone.
• the administration of gepirone or a bioactive gepirone metabolite includes the administration of any active salt form, hydrate form, enantiomeric form or mixture, or crystal form of the compound.
• the extended-release oral dosage form of gepirone of the present invention may be made by the following procedure: (i) admixing all or apart of components (a) through (f), (ii) blending the mixture, (iii) adding a part of or the remainder (if any) of components (a) through (f), (iv) blending the mixture (if remainder added during (iii)), (v) slugging, (vi) milling, (vii) adding the remainder of the lubricant (component (f); if part reserved during (i) and (iv)), (viii) blending the mixture; (ix) compressing the final finished tablet blend.
• the following procedure is followed to make the inventive extended-release oral dosage form of gepirone: i) admixing all of component (a), all of component (c), all of component (e), and 20% of the total concentration of component (b); ii) blending the mixture from (i); iii) adding to the blend from (ii) all of component (d), half of the total concentration of component (f), and the remaining 80% of the total concentration of component (b); iv) blending the mixture from (iii); v) slugging the blend from (iv); vi) milling the slug from (v); vii) adding the remaining 50% of component (f) to the milled slug from (vi); viii) blending the mixture from (vii); ix) compressing the blend from (viii) into the final desired form.
• the resultant blends are compressed in step (ix) into tablets or into micropellets. If micropellets are made, they are optionally overcoated with conventional coating adjuvant(s) and then tableted or filled into capsules. In the case where an enteric coating is desired, this coating would typically be added following step (ix).
• each of the above-described manufacturing processes may be scaled-up to an industrially applicable scale and is in no way limited to individual dosage preparation methods. It is also contemplated that alterations to each step (individually or collectively) may be made to facilitate the production of the inventive extended-release oral- dosage form of gepirone, so long the modifications do not alter the composition of the final product beyond the tolerance limits described above or the bioefficacy of the resultant product.
• Example 1 Dissolution profiles for the 60-mg formulation vs. the 20-mg formulation
• Fl and F2 provide insight and/or a measure of the distribution of results among batches. 2
• the criteria corresponds to acceptable Fl and F2 value ranges.
• the dose-normalized C max was calculated as C max /Dose.
• the slope ( ⁇ ) of the terminal log-linear phase of the concentration- versus-time curve was determined by linear regression.
• the procedure continued, adding preceding data points one at a time and fitting the regression equation, until C max occurring at the t max was reached.
• the terminal log-linear portion is then defined by the data yielding the smallest mean square error (MSE) term in the regression analysis.
• MSE mean square error
• the terminal elimination rate constant ( ⁇ z) was defined as - ⁇ from which the elimination half-life (ty 2 ) was calculated as Ioge2/ ⁇ z. Concentrations lower than LOQ in the elimination phase were ignored.
• the AUC from zero to ti as t was calculated by means of the linear trapezoidal rule, where ti ast represented the last time point with a measurable concentration within a subject.
• the dose-normalized AUCo-tiast was calculated as AUC 0- ti a st/Dose.
• the dose-normalized AUCo -00 was calculated as AUCo- ⁇ /Dose.
• the administered dose of gepirone was expressed as a free base. The amount free bases of gepirone was also used for CL app calculation of the 1-PP and 3'-OH gepirone metabolites.
• the weight-normalized CL app was calculated as CL app divided by the body weight
• V ZjaPP The weight-normalized V ZjaPP was calculated as V Z;app divided by the body weight (kg).
• dn-C max dn-AUC 0 .oo
• dn-AUCo-tiast 0.80-1.25 was used as acceptance range.
• the formulations were declared bioequivalent with respect to the tested parameters if the 90% confidence interval was fully contained within the acceptance range. This was done for gepirone, 1-PP and 3'-OH gepirone.
• classical hypothesis testing was performed on the logo-transformed values using the same ANOVA models as for the bioequivalence testing.
• SR 2 total sample variance (i.e. sum of within- and between-subject variances) of the reference treatment based on loge transformed parameters.

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• 2004
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