Gastric Ulcer Prevention by Lansoprazole

AUTHORS

Byung Soh Min1, Kang Young Lee1 and Nam Kyu Kim1*

1Department of Surgery, College of Medicine, Seoul, South Korea

Introduction

Sustained Release Formulation

For decades an acute or chronic illness is being clinically treated through delivery of drugs to the patients in form of some pharmaceutical dosage forms like tablets, capsules, liquids, creams, pills, aerosols, injectable, and suppositories with their main discrepancy to maintain drug levels within the therapeutic range. However, these conventional dosage forms have some drawbacks. Multiple daily dosing is inconvenient to the patient and can result in missed doses, made up doses and patient incompliance with the therapeutic regimen. When conventional immediate release dosage forms are taken on schedule and more than once daily, there are sequential therapeutically blood peaks and valley associated with taking each dose. It should be emphasized that the plasma level of a drug should be maintained within the safe margin and effective range. For this, proper and calculated doses of the drug need to be given at different time interval by conventional dosage form.1

This is possible through administration of conventional dosage form in a particular dose and particular frequency to provide a prompt release of drug. Therefore to achieve as well as to maintain the concentration within the therapeutically effective range needed by the treatment by repeated administration a day, results in a significant fluctuation in a plasma drug level, leads to several undesirable toxic effects, and poor patient compliance.2The loopholes of the conventional dosage forms lie in their inability:

Controlled drug delivery systems have been introduced to overwhelm the drawback of fluctuating drug levels associated with conventional dosage forms. Various terms like 'smart', intelligent', 'novel', therapeutic have been assigned to controlled release systems.

Methods and Materials

The following materials of Pharma grade or the best possible Laboratory Reagent grade were used as supplied by the manufacturer.

S.No

CHEMICAL NAME

SOURCE

PURPOSE

1

Lansoprazole

MSN Laboratories, Hyderabad, India

     

       Drug

2

Ethyl Cellulose

SD Fine chemical Ltd, Mumbai, India

 

      Polymer

3

Dichloro Methane (DCM)

SD Fine chemical Ltd, Mumbai, India

 

      Polymer

4

 Paraffin Liquid (light)

SD Fine chemical Ltd, Mumbai, India

    

      Solvent

5

Span 80

SD Fine chemical Ltd, Mumbai, India

  

      Stabilizer

6

N- Hexane

SD Fine chemical Ltd, Mumbai, India

     

      Solvent

8

Potassium dihydrogen Phosphate

SD Fine chemical Ltd, Mumbai, India

 

      Buffer                                                               ingradient

9

 NAOH pellets

SD Fine chemical Ltd, Mumbai, India

 

      Buffer ingradient

 

Table 1:  List of materials used and supplier

LANSOPRAZOLE

Lansoprazole belongs to class of antisecretory compounds, the substituted benzimidazoles that donot exhibit antocholinergic or histamine H2 receptor antagonist properties but rather supress gastric acid secretion by inhibition of the H+, K+ ions.

Lansoprazole has been charecterised as a gastric acid pump inhibitor in that it blocks the final step of acid production. This effect is dose related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. 

Analytical method development

Preparation of buffer pH 6.8

50ml of the potassium dihydrogen phosphate (0.2M) was placed in 200ml volumetric flask and to it 22.4ml of sodium hydroxide solution (0.2M) was added and the volume was made upto 200ml with distilled water.

Preparation of standard solution of lansoprazole:

Procedure: Accurately weighed 100 mg of lansoprazole drugwas dissolved in 100 mL of (Conc. 1000 µg/mL). From this solution, 10 mL was pipetted out into 100 mL volumetric flask and volume was made up to with methanol (Conc. 100 µg/mL). Further 10ml aliquot was taken from this solution (100μg/ml) and diluted to 100ml with methanol to give 10μg/ml standard solution of drug.

Similarly, standard stock solution was prepared in phosphate buffer pH 6.8 and methonol.

Preparation of microspheres

For the preparation of microspheres the double emulsion method was used as suggested by Rama Rao et al. (2005) with slight modifications. The polymer was dissolved in a mixed solvent system (MSS) of acetonitrile and dichloromethane. To this polymer solution glipizide was added and mixed. Then metformin was dissolved separately in 3 ml of distilled water and added to the polymer solution while stirring to form a primary emulsion. This primary emulsion was stirred at 450 rpm for 15 min using a mechanical stirrer. Then, this w/o emulsion was poured into liquid paraffin containing Span180 as the surfactant. This was stirred using a mechanical stirrer for 3 h, for the complete evaporation of the solvent. 10 ml of n-hexane was added as the non solvent after 2 h of the stirring process. 47

Treatment and randomization

All patients who met the inclusion and exclusion criteria received a 1 week course of antihelicobacter therapy containing lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg, given twice daily. This was followed by treatment with lansoprazole 30 mg, given daily for 4 weeks. Repeat endoscopy was performed at the end of treatment to check for healing of ulcers and eradication of H. pylori using the methods described above. Patients with unhealed ulcers would be given 30 mg of lansoprazole daily for another 4 weeks. Patients who failed H. pylori eradication, defined as a positive rapid urease test or histology, would receive another 1 week course of triple therapy containing ranitidine bismuth citrate 400 mg, amoxicillin 1 g and metronidazole 400 mg, given twice daily. Patients with unhealed ulcers and two unsuccessful eradication treatments of H. pylori were taken out of the study.

Results and Discussion

In the present investigation an attempt has been made to formulate microspheres of lansoprazole by using biocompatible polymer like ethyl cellulose and hydroxypropyle methyle cellulose as carrier for sustained release. Microspheres were prepared by double emulsion solvent evaporation method. Prepared microspheres are subjected for characterization and evaluation studies.
Characteristics of patients

Among 102 patients screened during the study period, 45 were suitable for entry into the trial and were given a 1 week course of triple therapy, followed by treatment with lansoprazole. Reasons for exclusion are given in Figure 1. Two patients had persistent H. pylori infection after the first course of eradication therapy; they received the second antihelicobacter therapy and H. pylori was eradicated in both patients. Two patients had persistent ulcers after repeated anti‐ulcer treatment and were excluded from the study. The remaining 43 patients were given naproxen 750 mg daily and randomly assigned to receive lansoprazole treatment (n = 22) or no treatment (n = 21).


Lansoprazole group (n = 22)

No treatment group (n = 21)

 

Mean age, years (range)

67.1 (41–78)

70.2 (43–78)

 

Age ≥ 65 (%)

13 (59.1)

12 (57.1)

 

Female gender (%)

8 (36.4)

11 (52.4)

 

Diagnosis (RA/OA/other)

6/15/1

4/17/0

 

Smoking (%)

3 (13.6)

2 (9.5)

 

Alcohol (%)

2 (9.1)

2 (9.5)

 

Co‐morbid illnesses (%)

8 (36.3)

9 (42.9)

 

Location of ulcer (gastric ulcer/duodenal ulcer)

18/4

15/6

 

Ulcer size

11.2 ± 4.0

10.3 ± 4.3

 

Bleeding on presentation (%)

17 (77.3)

13 (61.9)

 

Characteristics of ulcer bleeding

 

Admission haemoglobin, g/dL

9.5 ± 1.5

9.3 ± 1.2

 

Transfusion required, units

1.1 ± 1.3

1.4 ± 1.2

 

 Before endoscopy

0.76 ± 1.03

1.0 ± 1.0

 

 After endoscopy

0.29 ± 0.47

0.38 ± 0.51

 

Median ulcer size, mm (range)

10.0 (5–20)

10.0 (5–20)

 

Admission pulse ≥ 100 beats/min (%)

4 (23.5)

3 (23.1)

 

Admission systolic BP < 100 mmHg (%)

4 (23.5)

2 (15.4)

 

Shock at presentation * (%)

4 (23.5)

2 (15.4)

 

Serum urea > 10 mmol/L

10 (58.8)

10 (76.9)

 

Location of ulcer (gastric ulcer/duodenal ulcer)

14/3

10/3

 

Endoscopic haemostasis (%)

7 (41.2)

3 (23.1)

 

Data of standard graph of lansoprazole in ph.6.8 phosphate buffer

 

    Concentration

        (ug/ml)

 Absorbance in

phosphate buffer        

          10

      0.083

          20

      0.162

           30

      0.243

           40

      0.325

           50

      0.398

           60

      0.482

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Standard graph of lancoprazole in phosphate Buffer of pH

    PREFORMULATION STUDIES

Preformulation study for lansoprazole has been performed to know the drug physical properties so as to design it to a suitable formulation.

Physical property

lansoprazole

Empirical Formula

C4H11N5.HCl

Molecular Weight

369.36 daltons

Color and odour

White brownish colour powder

Taste

Slightly bitter in taste

Appearance

Crystalline powder

 

 

 

 

 

 

 

 

 

 

Table: Description data of lansoprazole

SURFACE MORPHOLOGY BY SEM

Particles in spherical shape

Conclusion

From the study it is evident that promising sustained release microspheres of lansoprazole may be developed by W/O/O double emulsion solvent diffusion technique by using ethyl cellulose and hydroxyl prople methyle cellulose polymer.

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