Enhanced Oral Bioavailability of Chlormadinone Acetate through a Self-Microemulsifying Drug Delivery System for a Potential Dose Reduction.

Chlormadinone acetate (CMA) is a derivative of the naturally secreted hormone progesterone and exhibits reliable contraceptive and non-contraceptive benefits. Although the marketed product of CMA as oral tablets under the trade name Belara® has been highly successful, there is still room for further improvements in oral bioavailability and a reduction in the clinical dose to decrease related adverse effects. In the current study, a CMA-based self-microemulsifying drug delivery system (SMEDDS) was developed using 32% ethyl oleate as an oil phase, 40% Tween-80 as a surfactant, and 12% Transcutol P combined with 16% PEG400 as a cosurfactant, resulting in spherical droplets with a z-average particle size of 38.92 nm and an average zeta potential of - 3.18 mv. The in vitro release rate of CMA from CMA-SMEDDS in different media (distilled water, HCl solution at pH 1.2, phosphate buffers at pH 4.5 and pH 6.8) was significantly faster than that from Belara® in the first 15 min. A pharmacokinetic study in rats showed that the Cmax and AUC of CMA-SMEDDS were significantly higher (P < 0.01) than those of Belara®, with a 1.98-fold increase in oral bioavailability. In comparison with Belara®, the developed CMA-SMEDDS showed promising release profiles both in vitro and in vivo, which could potentially be useful in enhancing oral bioavailability and reducing the clinical dose of CMA.

Comparative effects of chlormadinone acetate and its 3alpha- and 3beta-hydroxy metabolites on progesterone, androgen and glucocorticoid receptors.

AIM/METHODS: In vitro binding tests to human receptors and in vivo functional activities in animals were used to compare the effects of the progestin chlormadinone acetate (CMA) and its 3alpha- and 3beta-hydroxy metabolites (3alpha-OH-CMA and 3beta-OH-CMA) on progesterone, androgen and glucocorticoid receptors. RESULTS: CMA, 3alpha-OH-CMA, 3beta-OH-CMA and the reference progestin R5020 bound to human progesterone receptor with Ki values of 2.5 nm, 13 nm, 6.0 nm and 4.3 nm, respectively. Binding affinities to the human androgen receptor were characterized by Ki values of 3.8 nM for CMA, 83 nM for 3alpha-OH-CMA, 20 nM for 3beta-OH-CMA and 2.9 nM for the reference androgen methyltrienolone. The Ki values for binding to the human glucocorticoid receptor were 16 nM for CMA, 69 nM for 3alpha-OH-CMA, 21 nM for 3beta-OH-CMA and 1.2 nM for the glucocorticoid dexamethasone. In the rabbit endometrial proliferation test CMA, 3alpha-OH-CMA and 3beta-OH-CMA (5 and 45 microg/kg p.o. for 5 days) had similar progestomimetic activities. CMA, 3alpha-OH-CMA and, to a lesser extent, 3beta-OH-CMA (4.64 and 21.5 mg/kg p.o. for 7 days) inhibited testosterone-stimulated growth of prostate and seminal vesicles in castrated rats showing antiandrogenic activities. Glucocorticoid properties were demonstrated for CMA and 3alpha-OH-CMA (21.5 and 100 mg/kg p.o. for 6 days) but not for 3beta-OH-CMA as reduction in thymus and adrenal gland weights in immature rats. CONCLUSION: Binding assays at human receptors showed similarly high affinities of CMA with the progesterone and androgen receptors and a 5 times lower affinity with the glucocorticoid receptor. At all receptor types, CMA had the highest, 3alpha-OH-CMA the lowest and 3beta-OH-CMA an intermediate affinity. Animal studies revealed progestomimetic and antiandrogenic activities of CMA, 3alpha-OH-CMA and 3beta-OH-CMA and glucocorticoid activities of CMA and 3alpha-OH-CMA.

Characterization of the stimulatory effect of medroxyprogesterone acetate and chlormadinone acetate on growth factor treated normal human breast epithelial cells.

OBJECTIVE: Evidence is increasing that adding progestogens to hormone replacement therapy may be more harmful than beneficial, however it is debatable whether all progestogens act equally on breast cells. Mitogenic growth factors from stromal breast tissue are important in growth-regulation of breast cells, and may modify responses to progestogens. We investigated the effect of two C-21 derivatives, medroxyprogesterone acetate (MPA) and chlormadinone acetate (CMA) on growth-factor treated normal breast epithelial cells and tried to explore the underlying mechanisms of proliferation. METHOD: MCF10A (human epithelial, estrogen- and progesterone-receptor negative normal breast cells) were incubated with MPA or CMA at 0.1 and 1 microM for 7 days with the growth factors (GFs) EGF, bFGF and IGF-I at 1pM. The same combinations, as well as growth factors alone, were also incubated with the proliferation inhibitors PD98059 and LY294002 at 1 microM for 4 days. Cell proliferation rate was measured by the ATP-assay. RESULTS: MPA 0.1 and 1 microM, and CMA 1 microM in combination with GFs both significantly increased cell proliferation rate, with MPA having the greatest effect. MPA- and CMA-induced proliferation of GF stimulated cells was blocked by both PD98059 (selective inhibitor of MAP kinases) and LY294002 (phosphatidylinositol 3-kinase inhibitor); GF stimulated cells could not be significantly reduced by any of the inhibitors used. CONCLUSION: MPA and CMA have a stimulatory effect on benign growth factor stimulated MCF10A cells, possibly via activation of MAP kinase and subsequent substrates and activation of PI3-kinase. GF induced proliferation appear to be mediated by pathways other than those investigated here. Growth factors and progestogens therefore have an additive, synergistic effect on cell proliferation, eliciting their effects via different pathways.

Metabolism of osaterone acetate in dogs and humans.

Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway.

Evidence that chlormadinone acetate exhibits antiandrogenic activity in androgen-dependent cell line.

Chlormadinone acetate (CMA), like other 17-hydroxyprogesterone derivatives, is thought to be a potential antiandrogen on the basis of its effect on spontaneous benign prostatic hyperplasia (BPH) in dogs. This work was undertaken to find out whether CMA presents antiandrogen activity in human androgen-dependent cell line. For this purpose, we used PALM cells, the PC-3 cell line stably transfected with human androgen receptor and a luciferase gene under transcriptional control of MMTV. Potential antiandrogenic activity was compared with that of cyproterone acetate (CPA), a standard steroidal antiandrogen. Both compounds were tested in competitive binding assays at 37 degrees C in the presence of 1 nM of [3H] R1881, a synthetic and non-metabolizable androgen. Their impact on AR transcriptional activity was evaluated by the measure of luciferase activity in the presence of R1881 with increasing concentrations of CMA or CPA (10(-8)-10(-6) M). In whole cell binding assays, competitive studies revealed that the Ki for CMA was 3.3 +/- 1.5 x 10(-8) M (versus 7.2 +/- 1.3 x 10(-8) M for CPA). Inhibition of AR transcriptional activity was 40 +/- 5% for CMA (3 x 10(-7) M) versus 59 +/- 6% for CPA at the same concentration. Moreover, CMA caused a slower import of green fluorescent protein (GFP)-AR to the nuclei of COS-7 cells than R1881. These data show that CMA exerted a competitive binding for AR and significantly decreased the AR transcriptional activity. In conclusion, this synthetic progestin presents simultaneous antiandrogenic activity that could be helpful as a new therapeutic option in women with luteal defect along with clinical signs of hyperandrogenism.

Characterizations of mouse hepatic microsomal monooxygenase catalyzing 11beta-hydroxylation of osaterone acetate.

Osaterone acetate (17alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione, OA) is a new steroidal antiandrogen. There is a marked species difference in the metabolism of OA in that 11beta-hydroxylated metabolites are found in the plasma, feces, and urine of mice after oral administration of OA, but there is very little metabolism in rats and humans. OA reduces the adrenal gland weight in mice, but not in rats, and this effect in mice might be explained by the species difference in 11beta-hydroxylation activity. The objectives of this study were to elucidate the enzyme(s) involved in this particular oxidation and to explain the species difference observed. Mouse hepatic microsomes oxidize OA to 11beta-OH OA, and this oxidation requires NADPH as a cofactor. The use of various competitive and allosteric inhibitors of cytochrome P450 and flavin-containing monooxygenase (i.e. CO, N-octylamine, and methimazole) showed that the oxidation of OA was catalyzed by cytochrome P450. In microsomes from mice pretreated with phenobarbital (a CYP2B-selective inducer), 3-methylcholanthrene (a CYP1A-selective inducer), pregnenolone-16alpha-carbonitrile (a CYP3A-selective inducer), and EtOH (a CYP2E-selective inducer), an increase in the rates of oxidation was seen only in microsomes from EtOH-treated animals. However, metyrapone, a selective inhibitor for enzymes of the cytochrome P45011B and P4502B family, inhibited mouse hepatic microsomal 11beta-hydroxylation by < 30%. The results obtained showed that the production of 11beta-OH OA may be catalyzed by a novel cytochrome P450 in mouse liver.

[The effect of antiandrogen TZP-4238 on corticosteroid hormone in the dog].

We studied the adrenosuppressive effect of antiandrogen TZP-4238 and its metabolites. The binding affinity for the corticosteroid receptor using rat hepatic cytosol was in the order 11-OH TZP-4238 > 11, 15-(OH)2 TZP-4238 >> TZP-4238 > or = 15-OH TZP-4238 > 11-keto TZP-4238. Male beagle dogs aged 1-6 years were randomly divided into TZP-4238 (0.05, 0.5mg/kg) treatment groups and CMA (0.5mg/kg) treatment group. Each group was administered the drug per os every day for 8 weeks. Plasma cortisol, TZP-4238 and its metabolite levels were measured by on-line coupling of liquid chromatography with thermospray or atmospheric pressure ionization mass spectrometry using selective ion monitoring (LC-MS/SIM). LC-MS/SIM provided a sensitive and reliable method of unequivocal confirmation of the presence of steroidal drugs in the plasma. The plasma cortisol level was lowered below 1 ng/ml at 1 week after oral administration of TZP-4238 at 0.5mg/kg or CMA at 0.5mg/kg. The decline continued throughout the treatment for 8 weeks. Upon termination of administration, the cortisol level returned to the normal level (6ng/ml) by 4 weeks. However in the group given 0.05mg/kg TZP-4238, the cortisol level remained within the normal range. To analyze the cortisol decreasing mechanism, we administered TZP-4238 at 0.5mg/kg for 7 days to one beagle dog. When the plasma 11-OH TZP-4238 level was increased, the cortisol level decreased time dependently and the concentration of plasma 11-OH TZP-4238 which induced 50% inhibition was 2ng/ml. The decrease in the plasma cortisol level was highly correlated to the extent of the increase of the plasma 11-OH TZP-4238 (r2 = 0.840). We conclude that the adrenosuppressive effect of antiandrogen TZP-4238 is not due to TZP-4238 itself but its metabolite 11-OH TZP-4238.

[High-dose progestational contraception: advantages]. / Contraception macroprogestative: avantages.

In spite of the nearly total effectiveness of classic estrogen-progestogen oral contraception and its good overall tolerance, in a not inconsiderable number of situations yet, it is not possible to resort to it. These situations are the following: high blood pressure, hyperlipemia, diabetes, minor mastopathy, premenstrual tension either spontaneous or under estroprogestogen therapy. Macroprogestational contraception using either pregnanes (chlormadinone acetate) or nor-pregnanes, promegestone, nomegestrol acetate, can be then the right solution. Clinical and metabolic tolerance is excellent. In the occurrence of hypoestrogeny symptoms, a combination of nomegestrol acetate-estradiol 17 beta, transdermally administered, has given top results in a preliminary study.

[The effects of anti-androgen TZP4238 (17 alpha-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione) and its related compounds on the in vitro formation of androgen-receptor complex].

It was reported that a new steroidal anti-androgen, TZP4238 (17 alpha-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione), was 10 times stronger than chlormadinone acetate (CMA) as the in vivo anti-androgenic potential. To confirm this result, the effect of TZP4238 and CMA on ventral prostates of intact rats, or castrated ones treated by testosterone, was investigated. Our experiments demonstrated that TZP4238 was 3-5 times stronger than CMA. The effects of this compound on the androgen-receptor complex formation in the human and rat prostates were investigated and compared to the other anti-androgen and related compounds. An aliquot of cytosol or KCl extract from rat or human prostate was incubated with [3H]R1881 in the presence of various tested compounds. By means of dextran coated charcoal assay and sucrose density gradient centrifugation analysis, TZP4238 and TZP4239 showed a stronger inhibitory effect than other compounds except dihydrotestosterone. Judging from all these results, it was estimated that TZP4238 was 2-3 times stronger than CMA. The Scatchard plot analysis revealed that the inhibitory effect of TZP4238 was a competitive type. Between CMA and TZP4238, the difference of in vivo anti-androgenic potential was not identical with that of the inhibitory effect on the androgen-receptor complex formation.

Progesterone derivatives that bind to the digitalis receptor: effects on Na+,K+-ATPase and isolated tissues.

The steroid nature of the cardiac glycosides (CG) suggests that an endogenous steroid (or steroids) may be the natural ligand for the specific receptor site, i.e., Na+,K+-ATPase. Derivatives of progesterone (PROG) that compete in a [3H]ouabain radioreceptor binding assay (RRA) are characterized by 17 alpha-acetylation and modifications in the B ring. Chlormadinone acetate (CMA) is the most potent analog identified thus far, having about one-twentieth the RRA potency of ouabain. CMA interacts at the ouabain site on Na+,K+-ATPase, inhibits the enzyme in the same rank order of species sensitivity as do the CG, and inhibits the sodium pump in vitro in guinea pig atrium and perfused heart, cardiac myocytes, rat diaphragm, and red blood cells. CMA does not cross-react with digoxin antiserum, which indicates that CG antibodies are not necessarily directed at molecular determinants of biological activity. By crystallographic analysis, the 20-carbonyl moiety in CMA is seen spatially oriented so as to be equivalent to the lactone 23-oxygen atom in the CG. CMA exerts primarily cardiodepressant effects, in accordance with the often-reported similar action of PROG. Negative inotropy may be mediated other than by Na+,K+-ATPase because PROG itself has no significant CG-like actions. Positive inotropy by CG, cardiodepression by CMA and PROG or low concentrations of CG, occasional transient enhancement of contractility by CMA, and pump stimulation by low concentrations of CMA or CG may reflect different affinities of the compounds for sites that mediate Na+,K+-ATPase/pump inhibition, positive inotropy, and negative inotropy. Thus, PROG derivatives related to CMA appear to be likely candidates for endogenous digitalis-like hormones. Body tissues possess the enzymes for conversion of PROG to derivatives related even more closely than the semisynthetic CMA to the CG configuration.

Chlormadinone acetate, a progesterone derivative that binds to the digitalis receptor, inhibits the sodium pump in the isolated rat diaphragm.

Rb+ uptake, intracellular Na+ and K+ levels, and the tissue-medium distribution of the nonmetabolized glucose analog, 3-O-methyl-D-glucose (3-MG) were measured in rat diaphragms incubated with chlormadinone acetate, 6-chloro-4,6-pregnadien-17-ol-3,20-dione 17-acetate (CMA), in the presence and absence of ouabain. CMA in concentrations of 5 X 10(-7) M or higher significantly depressed 86Rb uptake, and promoted an increase in internal Na+ and a decrease in internal K+, indicating inhibition of the sodium pump. Sugar transport in resting muscle parallels the changes in internal Na+ levels and is an additional indicator of sodium pump activity. Equilibration of 3-MG between tissue and medium was accelerated by CMA, in parallel to the rise in internal Na+ level. Effects of CMA on Na+ levels and sugar transport, but not on Rb+ uptake, were additive to those of various concentrations of ouabain, suggesting interaction with sites not affected by ouabain. These results on diaphragm muscle confirm our previous studies on isolated cardiac muscle preparations showing that CMA, added to the aqueous bathing medium, inhibits the sodium pump in intact muscle tissues.

Progesterone derivatives that bind to the digitalis receptor: effects on 86Rb uptake and contractility in the isolated guinea pig heart.

Chlormadinone acetate, 6-chloro-4,6-pregnadien-17 alpha-ol-3,20-dione 17-acetate (CMA), a progestin that binds to the cardiac glycoside (CG) receptor, inhibits 86Rb uptake in slices of the guinea pig heart (Langendorff preparation), previously perfused with the steroid in Krebs-Henseleit-bicarbonate with or without 0.125% serum albumin. CMA consistently inhibits 86Rb uptake at low concentrations, less than 10(-8) M, is more potent than ouabain in this regard, and at these concentrations usually does not affect contractility, although occasional instances of transient positive inotropy occur. At higher concentrations, (10(-7) and 10(-6) M) uptake of 86Rb by CMA is depressed further and is usually accompanied by diminished contractile force. CMA was reduced to the 3 beta-hydroxy derivative and converted to the more water-soluble 3 beta-hemisuccinate (CMA-S). Occasional positive, although transient, increases in contractile force were elicited by CMA-S, but cardiac depression predominated, and higher concentrations induced cardiotoxicity. The addition of 10(-7) to 10(-6) M CMA-S to perfusion medium containing a cardiostimulant concentration (10(-6) M) of ouabagenin resulted in depression of contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

[The in vivo metabolism of chlormadinone acetate in guinea pig and the uptake of testosterone-3 H and chlormadinone acetate-3 H in prostate of castrated male rat (author's transl)].

The metabolic fate and distribution of the anti-androgenic agent, 17 alpha-acetoxy-6-chloropregna-4, 6-diene-3, 20-dione (chlormadinone acetate, CMA), was investigated using guinea-pigs and rats. In order to elucidate the metabolic outcome, chlormadinone acetate was labelled with 3H at position C-1 and with deuterium at methyl moiety of the 17alpha-acetate. Guineapigs were maintained for 7 days on a diet containing 1% chlormadinone acetate having a ratio of d2/d0=1 and then for 1 day on a diet containing 1% chlormadinone acetate having radioactivity. The isolation and purification of the urinary and fecal metabolites were usually carried out in the manner shown in Fig. 1 and 2. The metabolites identified were as follows: the parent drug, monohydroxychlormadinone acetate having the additional hydroxy function in the steroid skeleton, 15 beta-hydroxy, 2 alpha-, 2 beta-hydroxy and unknown position, dihydroxy chlormadinone acetate, 2 alpha-, 3 beta-dihydroxy, 2 alpha-, 3 alpha-dihydroxychlormadinone acetate. Further, three dechlornated and reduced metabolites were also isolated from urine and feces. These were 17 a-acetoxy-5a-pregnane-3 beta-ol-20-one and its isomer, and 17-acetoxy-5 beta-pregnane-2 beta, 3 beta, 15a-triol-20-one. But 3 beta-hydroxychlormadinone acetate possessd with anti-androgenic activity, one of the main metabolites in humans and rats, was not found in the excreta of the guinea-pigs. However, the main metabolite on the prostate of the guinea-pigs and rats and 3 beta-hydroxychlormadinone acetate. Chlormadinone acetate causes regression of the seminal vesicle and prostate in oral administration to a mammalian. It was therefore hypothesized that chlormadinone acetate might inhibit the uptake and retention of testosterone in these tissues. To elucidate this hypothesis, the accumulation of testosterone-3H and chlormadinone acetate-3H in several organs was determined on castrated rats and normal rats, respectively. When 1.0 muM of testosterone-3H was given to the castrated rats, a maximal accumulation of radioactivity resulted in seminal vesicle and prostate at 15 approximately 120 min. While the treatment of chlormadinone acetate significantly prevented the accumulation of testosterone-3H in the seminal vesicle and prostate, but levels in fat and muscle were not evident. In addition, to prove the accumulation of chlormadinone acetate in androgen target tissues, 3 muM of chlormadinone acetate-3H was similarly administered to castrated rats. The uptake of chlormadinone acetate on the target organs was higher than that in normal rats at 5 approximately 30 min.

Binding of chlormadinone acetate to cytosol from human benign prostatic hypertrophy.

Chlormadinone acetate was bound to cytosol from the human benign prostatic hypertrophy in a high affinity fashion. The kd and number of maximum binding site of the binding were 5.4 +/- 0.7 X 10(-9) M and 67.9 +/- 5.8 fmol/mg protein, respectively. When compared with the binding to dihydrotestosterone, the Kd for chlormadinone acetate was greater. The number of maximum binding site for chlormadinone acetate was observed to be smaller than that for dihydrotestosterone, but these two values were not different statistically. The binding of chlormadinone acetate was inhibited significantly by the addition of R 1881 or cyproterone acetate. However, dihydrotestosterone revealed itself to be a weak inhibitor of the binding. The cytosol prelabelled with chlormadinone acetate was not bound to the nuclei of the human prostate.

Chlormadinone acetate.

PIP: This monograph on chlormadinone acetate (CA) includes chemical and physical data (synonyms and trade names), structural and molecular formulae and molecular weight of CA, chemical and physical properties of CA, and the production, use, occurrence, and analysis of CA. Production of CA, which is not known to occur naturally, occurs by treatment of 17-acetoxyprogesterone with ethyl orthoformate in the presence of an acid catalyst to produce the 3-enol ether of the corresponding 3,5-dione. Typical analytical procedures for determining CA as a bulk chemical are summarized tabularly. CA, before suspension from commercial use, was marketed as an ingredient in sequential oral contraceptives. It is approved as an estrus regulator in cattle feed. Biological data relevant to the evaluation of carcinogenic risk to humans are presented in brief. Experimental work with dogs, mice, and rats using oral administration has been done. When CA is combined with mestranol and given to mice, it increases the incidence of pituitary tumors in both sexes; combined with ethinylestradiol it increased the incidence of mammary tumors. When CA was given alone to dogs, mammary tumors developed. No human case reports or epidemiological studies on CA alone are available. Hence, it was concluded that there is limited evidence for the carcinogenicity of CA in dogs. In humans, oral contraceptives containing estrogens in combination with progestins have been related causally to increased incidence of benign liver adenomas and decreased incidence of benign breast disease, and so CA is implicated in this respect.^ieng

The effects of ergosterol on the response of female chicks to oral oestrogens and progestogens.

The chick-oviduct assay was used to investigate the effects of dietary ergosterol on the response to oral progestogens and oestrogens. 2. Progestogens alone had no effect on the oviduct but the hypertrophy due to oestrogen was greatly enhanced by simultaneous treatment with progestogen at all dose levels tested. 3. Ergosterol had no effect on any of the responses of the oviduct studied.

Implant pellets I: effects of compression pressure on in vivo dissolution of delmadinone acetate pellets.

A formulation containing 95% delmadinone acetate was compressed at three different pressures. These pressures resulted in a pellet density difference of 19%. In vivo dissolution profiles were determined for five lots of pellets. The pellets were implanted subcutaneously in rats, removed periodically, and assayed chemically for remaining steroid. The resulting data were fit, using the computer program NONLIN, to a dissolution model. The dissolution rate for the lot with the lowest density made at the lowest compression was statistically (p less than 0.05) different from the four other lots. A possible explanation for this increased dissolution rate could be that channeling occurs within the pellet, thereby increasing the effective dissolving surface. The results also indicate that equivalent dissolution rates between lots are reached at a certain compression and density.

PIP: Effects of compression pressure on in vivo dissolution of delmadinone acetate implant pellets were investigated in rats. A formulation containing 95% delmadinone acetate was compressed at 3 different pressures which resulted in a pellet density difference of 19%. Pellets from 5 different lots were implanted sc, removed periodically, and assayed chemically for remaining steroid. The results were fit, using the computer program NONLIN, to a dissolution model. The dissolution rate for the lot with the lowest density made at the lowest compression was significantly (p less than .01) greater than that of the other 4 lots. A possible explanation could be that channeling occurs within the pellet, thereby increasing the effective dissolving surface. These results also suggest that equivalent dissolution rates between lots are reached at a certain compression and density.