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Abstract
dopamine agonist, is derivative of lysergic
acid substituted with bromine that binds to dopamine-D2- receptors, it is a useful tool in the treatment of hyperprolactinaemia associated disorders, acromegaly and parkinsonism.
Prolactin concentration greater than 20 ng/ml on multiple occasions, are generally considered indicative of hyperprolactinemia. The most common disorders associated with hyperprolactinemia in females are; galactorrhea, menstrual irregularities (oligomenorrhea or amenorrhea) and infertility. In men, hyperprolactinemia has been reported to diminish libido and cause impotence, hypogonadism, infertility, galactorrhea or gynecomastia.
BCM is available in the market as oral tablets and capsules, only 28–30% of the oral dose is absorbed. The oral bioavialability is only 4.5-6% because of extensive presystemic metabolism by the liver. In addition to adverse side effects, commonly being postural hypotension, nausea, vomiting, fatigue, headaches, dizziness and faintness in 50% to 70% of women, cousing about 10% discontinue therapy.
To avoid many of these side effects, clinician trials have been focused on vaginal placement of commercial oral tablet. The drug is well absorbed through vaginal wall into the systemic circulation, the absorption is almost complete and the first pass through the liver is avoided, allowing use of a lower dosage and once daily treatment. However in practice, low acceptability of this route was noticed due to patient’s inconvenience about placement orally designed tablets inside the vagina, local irritation, excessive vaginal discharge and not solve the problem of hyperprolactinemia in virgins or men.
In the present study,
1-Vaginal and rectal suppositories of BCM as alternative to the oral dosage forms has been approached for the first time, since no suppository dosage form of the drug present in the market.
2- Hence the poor water solubility of the drug may affect its bioavailability, solid dispersion technique with certain water soluble carriers was approached to improve the solubility and dissolution of BCM. Furthermore, the physicochemical characteristics as well as the release of BCM from its dispersion systems were also investigated.
3- Clinical assessment appeared to be essential in hyperprolactinemic patients to confirm the usefullness of this new formulations.
Thus, the thesis comprises three chapters:
Chapter-1
Formulation and evaluation of bromocriptine mesylate suppositories.
Chapter-2
Improvement of solubility and dissolution of bromocriptine mesylate via solid dispersion technique .
Chapter-3
Clinical assessment of selected bromocriptine mesylate suppositories in hyperprolactinemic patients.
Chapter-1
Formulation and Evaluation of Bromocriptine Mesylate Suppositories
The aim of work in this chapter was to formulate BCM suppository dosage forms using water soluble and emulsion bases.
The water soluble bases selected were polyethylene glycols and gelatin (B.P) suppository bases. The emulsion bases consist of witepsol E75, witepsol H15 or cocoa butter as the oily phase, while water and PEGs as the aqueous phase. Certain surfactants such as tween 20 and span 60 used as emulsifying agents. Since the drug is hyDROPhobic, selection of fatty bases such as cocoa butter, witepsol H15 and suppocir AM were used just to predict the release pattern of BCM from these lipophilic bases.
I- Quality control testing of the prepared suppositories:
The physical properties of the prepared suppositories such as weight variation, hardness, disintegration time, melting range and content uniformity were studied.The results revealed that, the prepared suppositories comply with the B.P. requirements with regard to content uniformity and weight variation. In addition, most the suppository formulations exhibited suitable hardness and disintegration time.
II- In-vitro drug release in pH 4:
The in-vitro release of BCM (5mg) from the prepared suppositories were carried out using the beaker method in citrate buffer pH 4. The obtained results revealed that,
a) HyDROPhilic suppository bases:
The release of BCM from the water soluble suppository bases was higher than those obtained from suppositories prepared with emulsion or fatty bases. All formulations prepared with PEG bases gave more or less identical release pattern, relatively the formula which composed of 20% PEG 20000 and 80% propylene glycol (F5) gave the highest release pattern. With regard to gelatin bases, the best drug release was achieved from the formula which contained the highest percent of propylene glycol 40% (F18).
¬b) Emulsion suppository bases:
The release rate from emulsion bases was variable depending on composition of the suppository formula. Formulations contained PEG 1500 with PEG 600 or with propylene glycol as the aqueous phase gave the higher release rate than other formulations. Among these formulations, formula contained mixture of PEG 1500 and propylene glycol (F22) as the aqueous phase gave the highest release rate.
c) Fatty suppository bases:
Being hyDROPhobic, BCM has higher affinity to the lipophilic bases. As expected the release from such bases was very low and dependant on the melting behavior and chemical composition of the used base. Relatively witepsol H15 (F25) gave the highest release rate among fatty bases.
III- Kinetic analysis of release data:
The obtained results revealed that the release of BCM in citrate buffer pH 4 from PEG bases followed first order kinetics.The release from gelatin bases and from fatty bases followed diffusion mechanism. While the release from emulsion bases followed either first order or diffusion mechanism.
IV- In-vitro drug release in pH 7.4
Formula (F5) from PEG bases, formula (F18) from gelatin and formula (F22) from emulsion bases, were selected in terms of their in-vitro release in pH 4, simulating vaginal pH , to study the release rate of BCM in phosphate buffer pH 7.4, simulating rectal pH, under the same conditions.
The obtained results revealed that, the release rate of BCM from the emulsion base (F22) in phosphate buffer pH 7.4 much lower than in citrate buffer pH 4, while the other two bases (F5, F18) showed almost no release in phosphate buffer pH 7.4.
Chapter-2
Improvement of solubility and dissolution of bromocriptine mesylate via solid dispersion technique
Based on the in-vitro results at pH 7.4 where the drug nearly not released which may be due to its poor solubility in pH above its pka (4.9), the work in this chapter, was an attempt to improve the solubility and dissolution of BCM adopting solid dispersion technique. HyDROPhilic carriers vice, tween 20, tween 40, tween 80, brij 35, myrj 53, pluronic F68 and pluronic F-127, hydroxypropyl--cyclodextrin, methyl-- cyclodextrin and dimethyl--cylcodextrin at different ratios (1:1, 1:3, 1:5 and 1:7) of drug : carrier. BCM solid dispersions were prepared by the solvent evaporation method.
The prepared solid dispersions were evaluated for :
a) Solubility and dissolution studies:
Solubility results revealed a pronounced enhancement of BCM solubility in distilled water with the dispersion systems compared to the pure drug. The amount solubilized of the drug was increased by increasing the concentration of the carrier in the solid dispersion system. Pluronic F-127 (PF-127) exhibited the highest solubilizing effect in water, citrate buffer pH 4 and phosphate buffer pH 7.4 at drug:polymer ratio of 1:7. The same dispersion system exhibited the higher dissolution rate compared to its corresponding physical mixture (at the same ratio) or untreated drug.
Accordingly, BCM/PF-127 solid dispersion at 1:7 and the correponding physical mixture was selected for further investigations.
b) IR studies:
IR spectra proved that an interaction in the form of hydrogen bonding has been occurred in the solid dispersion system of BCM with PF-127 in ratio (1:7).The same interaction was observed with the corresponding physical mixture.
c) Differential scanning calorimetry (DSC):
The DSC thermograms showed complete disapperance of the drug melting point either in the solid dispersion or the physical mixture with PF-127 attributed to the conversion of BCM from a crystalline into amorphous form, on the other hand the absence of drug melting peak in the physical mixture may be due to the solubility of the drug in the molten carrier at higher carrier ratio.
d) X-ray diffractometry:
X-ray diffractograms showed that, the physical mixture of drug: PF-127 in weight ratio (1:7) still showing the characteristic drug peaks, while solid dispersion with the same ratio showed complete disappearance of drug characteristic peaks.This confirm the formation of the amorphous form of the drug when it was dispersed in PF-127.
e) Scanning electron microscopy:
The photomicrographs of PF-127, the drug and BCM/PF-127 (1:7) solid dispersion showed the absence of crystalline structure of the drug, which confirm the transformation of BCM from the crystalline to the amorphous form.
from collected data, it can be concluded that the hyDROPhilic carrier PF-127 at (1:7) drug: polymer ratio exhibited the most remarkable enhancing effect on solubility and dissolution of BCM.
Chapter 3
Clinical assessement of selected bromocriptine mesylate suppositories in hyperprolactinemic patients
This study was conducted in outpatient gynecological clinic of Assiut University Hospital, 76 female and 3 male hyperprolactinemic patients were selected. Patients were randomly assigned to one of the four studied groups. Group A received commercial oral tablets (Parlodel, 2.5 mg) vaginally, group B received BCM suppositories vaginally containing 2.5 mg of the untreated drug, group C received BCM suppositories vaginally containing BCM/PF-127 (1:7) solid dispersion equivalent to 2.5 mg of the drug, the last group D (included the 3 male patients) received the same formula of group C by the rectal route. The regiemen followed was one suppository once daily at bed time for one month, the prolactin concentration was measured before and after treatment by immunoassay method.
The clinical examination, serum prolactin measurment and patients complaints were recorded for each patient.
The results revealed that :
1-There was a significant DROP of serum prolactin levels in groups B,C and D, while group A showed a definite but insignificant DROP of serum prolactin after treatment.
2-The best clinical response in lowering serum prolactin concentration were obtained in patients of group C and group D which received vaginal and rectal suppositories containing BCM/PF-127 solid dispersion.
3-Group D which received the suppositories by rectal route showed more significant reduction in serum prolactin compared to group C which received the suppositories by vaginal route.
Therefore from this study it could be concluded that BCM solid dispersion with PF-127 (1:7) can be formulated into vaginal and rectal suppositories, thus improving the bioavailability, reduction of the dose to once daily and minimizing the side effects, in addition, these suppository formulations either vaginally or rectally can solve the problems of all hyperprolactinemic patients ( women, virgins or m