Włodzimierz Sawicki

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27μg/ml) over 24h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low Tg (113°C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8MPa(0.5)) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA.

The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9-9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td (302.3°C), an approach based on the drug crystallization from the supersaturated solid dispersion was selected to calculate the solubility of Td in the polymer. Annealing of the Td/PVP-VA solid dispersion (1:1, w/w) at selected temperatures above its Tg resulted in different stable solid dispersions. According to the Gordon-Taylor equation their new Tgs gave the information about the quantitative composition which corresponded to the thermodynamic solubility of Td in PVP-VA at given temperatures of annealing. The obtained relationship was fitted to the exponential function, with the calculated solubility of Td of 20.5% at 25°C. This value was in accordance with the results of hot stage polarizing light microscopy as well as stability tests carried out at 80°C and 0% RH, in which Td solid dispersions containing 10-20% of the drug were the only systems that did not crystallize within two months. A thermal analysis protocol utilizing a fast heating rate was shown to generate Td solubility data complementing the solid dispersion method. The Flory-Huggins model applied for the Td/PVP-VA system yielded the solubility value of 0.1% at 25°C, showing the lack of applicability in this case.

Growth factors, silver dressings and negative pressure wound therapy in the management of hard-to-heal postoperative wounds in obstetrics and gynecology: a review

PurposeThe last two decades witnessed the development of numerous innovative regimens for the management of patients with abnormally healing and infected wounds. Growth factors, negative pressure wound therapy (NPWT) and antiseptic dressings containing silver are examples of methods with best documented efficacy, being widely used in the treatment of acute and chronic post-traumatic wounds, burns and ulcers of various etiology. As far as obstetrics and gynecology are concerned, prevention and treatment of infected, hard-to-heal postoperative wounds is of crucial importance. This article reviews the available literature to discuss the possibilities for use, efficacy and cost-effectiveness of growth factors, NPWT and silver dressings in the treatment of difficult-to-heal postsurgical wounds in obstetrics and gynecology.Materials and methodsAn extensive search of the English and Polish literature via PubMed and EMBASE databases was undertaken for articles published between January 1960 and April 30, 2014 to identify articles that described and assessed use, efficacy and cost-effectiveness of growth factors, silver dressings and NPWT in patients with hard-to-heal postoperative wounds following obstetric or gynecological surgery.ConclusionsLiterature review regarding the use of growth factors, NPWT and silver dressings suggests that these methods may play an important role in the management of wounds after invasive obstetric and gynecological procedures. Obese patients, patients after vulvectomy or prior radiation therapy may benefit most, however, due to non-numerous randomized reports, prospective studies on the use of above-mentioned methods in the treatment of postsurgical wounds following obstetric and gynecological interventions are required.

Physicochemical properties of direct compression tablets with spray dried and ball milled solid dispersions of tadalafil in PVP-VA

The aim of this research was to develop immediate release tablets comprising solid dispersion (IRSDTs) of tadalafil (Td) in a vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA), characterized by improved dissolution profiles. The solid dispersion of Td in PVP-VA (Td/PVP-VA) in a weight ratio of 1:1 (w/w) was prepared using two different processes i.e. spray drying and ball milling. While the former process has been well established in the formulation of IRSDTs the latter has not been exploited in these systems yet. Regardless of the preparation method, both Td/PVP-VA solid dispersions were amorphous as confirmed by PXRD, DSC and FTIR. However, different morphology of particles (SEM) resulted in differences in water apparent solubility and disk intrinsic dissolution rate (DIDR). Both solid dispersions and crystalline Td were successfully made into directly compressible tablets at three doses of Td, i.e. 2.5mg, 10mgand20mg, yielding nine different formulations (D1-D9). Each of the lots met the requirements set by Ph.Eur. and was evaluated with respect to appearance, diameter, thickness, mass, hardness, friability, disintegration time and content of Td. IRSDTs performed as supersaturable formulations and had significantly improved water dissolution profiles in comparison with equivalent tablets containing crystalline Td and the marketed formulations. Tablets with both spray dried and ball milled Td/PVP-VA revealed the greatest improvement in dissolution depending on the investigated doses, i.e. 2.5mgand20mg, respectively. Also, dissolution of Td from Td/PVP-VA delivered in different forms occurred in the following order: powders>tablets>capsules.

Randomized Controlled Trial Evaluating Dialkylcarbamoyl Chloride Impregnated Dressings for the Prevention of Surgical Site Infections in Adult Women Undergoing Cesarean Section

Abstract Background: Surgical site infections (SSI) occur in 1.8%–9.2% of women undergoing cesarean section (CS) and lead to greater morbidity rates and increased treatment costs. The aim of the study was to evaluate the efficacy and cost-effectiveness of dialkylcarbamoyl chloride (DACC) impregnated dressings to prevent SSI in women subject to CS. Methods: Randomized, controlled trial was conducted at the Mazovian Bródno Hospital, a tertiary care center performing approximately 1300 deliveries per year, between June 2014 and April 2015. Patients were randomly allocated to receive either DACC impregnated dressing or standard surgical dressing (SSD) following skin closure. In order to analyze cost-effectiveness of the selected dressings in the group of patients who developed SSI, the costs of ambulatory visits, additional hospitalization, nursing care, and systemic antibiotic therapy were assessed. Independent risk factors for SSI were determined by multivariable logistic regression. Results: Five hundred and forty-three women undergoing elective or emergency CS were enrolled. The SSI rates in the DACC and SSD groups were 1.8% and 5.2%, respectively (p = 0.04). The total cost of SSI prophylaxis and treatment was greater in the control group as compared with the study group (5775 EUR vs. 1065 EUR, respectively). Independent risk factors for SSI included higher pre-pregnancy body mass index (adjusted odds ratio [aOR] = 1.08; [95% confidence interval [CI]: 1.0–1.2]; p < 0.05), smoking in pregnancy (aOR = 5.34; [95% CI: 1.6–15.4]; p < 0.01), and SSD application (aOR = 2.94; [95% CI: 1.1–9.3]; p < 0.05). Conclusion: The study confirmed the efficacy and cost-effectiveness of DACC impregnated dressings in SSI prevention among women undergoing CS.

Value of ultrasonography in the diagnosis of polycystic ovary syndrome – literature review

Polycystic ovary syndrome is a multi-factorial disease. Its etiopathogenesis has not been elucidated in detail. It is the most common endocrine disorder in women of child-bearing age. This disease entity is primarily characterized by disrupted ovulation and hyperandrogenism, but the clinical picture can be diversified and symptom intensity can vary. Currently, the sonographic assessment of ovaries is one of the obligatory criteria for the diagnosis of PCOS according to the Rotterdam consensus (2003) and Androgen Excess & PCOS Society (2006). This criterion is determined by the presence of ≥12 follicles within the ovary with a diameter of 2–9 mm and/or ovarian volume ≥10 cm3. Such an ultrasound image in one gonad only is sufficient to define polycystic ovaries. The coexistence of polycystic ovaries with polycystic ovary syndrome is confirmed in over 90% of cases irrespective of ethnic factors or race. However, because of the commonness of ultrasound features of polycystic ovaries in healthy women, the inclusion of this sign to the diagnostic criteria of polycystic ovary syndrome is still questioned. The development of new technologies has an undoubted influence on the percentage of diagnosed polycystic ovaries. This process has caused an increase in the percentage of polycystic ovary diagnoses since the Rotterdam criteria were published. It is therefore needed to prepare new commonly accepted diagnostic norms concerning the number of ovarian follicles and the standardization of the technique in which they are counted. The assessment of anti-Müllerian hormone levels as an equivalent of ultrasound features of polycystic ovaries is a promising method. However, analytic methods have to be standardized in order to establish commonly accepted diagnostic norms.

Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta

PurposeVarious studies in placental tissue suggest that diabetes mellitus alters the expression of glucose transporter (GLUT) proteins, with insulin therapy being a possible modulatory factor. The aim of the present study was quantitative evaluation of the expression of glucose transporters (GLUT-1, GLUT-4, GLUT-9) in the placenta of women in both, uncomplicated and diabetic pregnancy. Additionally, the effect of insulin therapy on the expression of selected glucose transporter isoforms was analyzed.MethodsTerm placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin-controlled gestational diabetes mellitus (GDMG2) (n = 6), and pre-gestational diabetes mellitus (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins.ResultsMorphometric analysis revealed a significant increase in the expression of GLUT-4 and GLUT-9 in insulin-dependent diabetic women (GDMG2 + PGDM) as compared to both, control and GDMG1 groups (p < .05). Significantly increased GLUT-1 expression was observed only in placental specimens from patients with PGDM (p < .05). No statistically significant differences in GLUT expression were found between GDMG1 patients and healthy controls.ConclusionsThe results of the study confirmed the presence of GLUT-1, GLUT-4 and GLUT-9 proteins in the trophoblast from both, uncomplicated and diabetic pregnancies. In addition, insulin therapy may increase placental expression of GLUT-4 and GLUT-9, and partially GLUT-1, in women with GDMG2/PGDM.

Expression of Glucose Transporter Proteins in Human Diabetic Placenta

Gestational diabetes mellitus and pregestational diabetes mellitus constitute carbohydrate metabolism disorders, which, if not diagnosed and adequately treated, lead to serious and often life-threatening pregnancy complications. According to a recently formulated hypothesis, some diabetes-related complications, such as fetal macrosomia, may be the result of disturbances in the transplacental transport of nutrients-in particular, excessive maternal-fetal glucose transfer. Throughout pregnancy, glucose flux across the placenta is mediated by the group of facilitative glucose transporters (GLUT), the expression of which in different placental compartments is the precondition for effective glucose uptake from maternal blood and its subsequent transfer to the fetal circulation. In diabetes-complicated pregnancies, the location, expression and activity of glucose transporters are modified to an extent that results in alterations in the maternal-fetal glucose exchange, potentially leading to an excessive supply of energy substrates to the fetus. This paper reviews the literature on the expression and activity of glucose transporter proteins-GLUT-1, GLUT-3, GLUT-4, GLUT-8, GLUT-9 and GLUT-12-in the human placenta, with a special focus on diabetes-complicated pregnancy. The characteristics of transporters in conditions of maternal normoglycemia and modifications occurring in the diabetic placenta are summarized, and the factors responsible for the regulation of the expression of selected isoforms are described. Finally, the impact of alterations in the placental expression of the aforementioned members of the GLUT family on intrauterine fetal development in pregnancies complicated by diabetes mellitus is discussed.

Spontaneous rupture of the pregnant uterus following salpingectomy: a literature review.

Background: Spontaneous rupture of the uterus is a life-threatening obstetric complication in rare cases associated with previously performed salpingectomy. Aim: This paper presents an analysis of uterine rupture cases during pregnancy in patients after surgical removal of the fallopian tubes. Methods: The English and Polish language literature was reviewed for studies published between January 1, 1980 and September 30, 2014 to identify articles that described rupture of the uterus in women with a previous history of salpingectomy. Results: Thirteen case reports and case series studies in 18 women were identified. 33% of cases of uterine rupture following salpingectomy occurred during intrauterine pregnancy, whereas the rest was associated with interstitial ectopic pregnancy. Laparoscopic salpingectomy more often resulted in rupture of the uterus during non-ectopic pregnancy as compared to laparotomy (4 vs. 2 cases, respectively). When interstitial pregnancies were excluded, uterine rupture was a cause of fetal death in 67% of reported gestations. There were no cases of maternal mortality. Conservative treatment was the preferred management option, and total hysterectomy was performed in only 2 patients. Conclusion: Particular attention should be paid to patients with a previous history of salpingectomy due to the risk of uterine rupture throughout the entire pregnancy.

Placental tumor (chorioangioma) as a cause of polyhydramnios: a case report

Placental chorioangioma is the most common type of placental tumor. It is usually symptomless and may be associated with serious maternal and fetal complication when it reaches a large size. We presented a case of an angiomatous type of placental hemangioma diagnosed in the second trimester of pregnancy in a patient with polyhydramnios. A normal volume of amniotic fluid was successfully achieved by three amnioreductions with conservative management. The size of the placental tumor remained the same from the time of diagnosis to the end of pregnancy. A term labor was uncomplicated and a healthy newborn was delivered. Macroscopic and microscopic examination of the placenta confirmed the diagnosis. Despite the rarity of placental tumors, they should be considered as differential diagnosis in cases of polyhydramnios.