Formulation and Evaluation of Naproxen Suppositories for Rectal Drug Delivery

Suppositories represent an important, yet underutilized, dosage form suitable for systemic and localized drug delivery, especially when oral administration is impractical. Rectal drug delivery offers benefits such as partial avoidance of hepatic first-pass metabolism, ease of administration in pediatric and geriatric patients, and suitability for drugs causing gastrointestinal irritation. Naproxen is a widely used NSAID with high plasma protein binding and good bioavailability. However, its oral use may lead to gastrointestinal disturbances. Developing a rectal suppository could mitigate these issues and offer controlled release profiles.

Definition: A suppository is defined in a fairly vague manner. Only the EP contains a separate chapter on rectal dosage forms among the USP, European, and Japanese Pharmacopoeias (USP, EP, and JP, respectively). A suppository is solely defined by the USP and JP as a dosage form designed for rectal administration. In order to deliver a local or systemic impact, suppositories are described as an administration method that is administered into the rectum or vagina.Depending on the point of reference, suppositories can be described in numerous ways. Functionally, they are best described as semi-solid dose forms utilizedto provide medications fortherapeutic action via rectal, vaginal, or urethral routes. They meltin the body temperature and then dissolved to give systemic and localized action and serve as an alternative to oral route of administration.

Ideal Properties of Suppositories:

Following should be the properties of suppositories:

• It should melt at body temperature or dissolve,or it should be dispersed in the body fluids. It should release there medicaments radially.
• It should be compatible with any medicament when added. Most importantly it should be non-toxic and non-irritant to the mucous membrane.
• It should not interfere in release or absorbance of drug.
• It should be stable on storage.
• It should not be softened or hardenedon storage.
• It must retain their shape and size. It should have kept their shape intact when handled.
• It should be stable when heated above its melting point.
• It should not adhere to the surface of the mould
• It should shrink sufficiently while removing from the mould.

Mechanism of Action :(7, 9)

A suppository will first dissolve in the liquid or melt on the mucous layer depending on whether it is hydrophilic or lipophilic. The osmotic properties of the dissolving vehicle cause water to be drawn to the rectum or vagina, and when the suppository melts and dissolves, the drugs it contains will diffuse out toward the mucosal epithelial surfaces. If the drug is water immiscible, it must first break free from the base of the suppository by the action of gravity or ambulation before it may begin to dissolve in liquid. The softening and dispersion of lipophilic melting suppositories are not dependent on the presence of fluid. The same method of medication administration is usedin suppositories, which dissolve when heated Showing Mechanism of Action

Fig No.1: Mechanism of Action Suppository

MATERIALS AND METHODS:

Materials Naproxen was obtained as a gift sample. PEG 400 and PEG 4000 were used as base materials. Other chemicals and reagents used were of analytical grade.

Preparation of Suppositories:

Suppositories were prepared by the fusion method using PEG 400 and PEG 4000 in varying ratios. The drug was incorporated into the molten base, which was then poured into lubricated molds and allowed to solidify.

Fusion Methods :-(10, 13)

Fig No. 2: Preparation of suppositories by fusion method

Fusion moulding involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the poured into a suppository mold. The fusion method can be used with all type of made from solid ingrediants and drug which are measured by weight. When they are mixed, melted,and poured into suppository mild cavities. They occupy a volume the volume of the mold cavity . Since the components are measured by weight but compounded by volume. Density calculation and mold calibration are required to provide accurate doses.

Need of Suppository :(2,10,14)

1. Two or more active ingrediants in a single dosage form for sequential release of these drugs and to avoid incompatibility between them.
2. Alternative form of oral medication for systemic action in patients who are in coma or who cannot tolerate oral medication due to periodical episodes of nausea and vomiting or pathological conditions of the gastrointestinal tract.
3. To reduce first pass metabolism.
4. To relieve and treat haemorrhoids .
5. To avoid first pass effect to improve drug bioavailability.
6. In this case of emergency administration there may be lower psychological and social barriers because of seriousness of the situation.
7. Research also suggests that taking a relatively constant environment for a drug to be delivered that rate of absorption may, however be lower than that of drugs taken by mouth.
8. Naproxen suppository used for inflammatory condition like arthritis (Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis).

Objectives:

• Systemic Drug Absorption – Some suppositories are designed for systemic effects, allowing the drug to enter the bloodstream via the rectal mucosa.
• Local Treatment – Used to treat conditions like hemorrhoids, constipation, and inflammation .
• Alternative to Oral Route – Useful for patients who have difficulty swallowing, are unconscious, vomiting, or have gastrointestinal issues that prevent oral drug absorption.
• Bypassing First-Pass Metabolism – Drugs absorbed rectally can partially bypass hepatic first-pass metabolism, leading to improved bioavailability.
• Sustained Drug Release – Some suppositories provide prolonged drug release for extended therapeutic effects.e

 Exprimental:

Composition of Naproxen Suppositories by CCD-

Table No. 1: Composition of Naproxen Suppositories by CCD

* All ingredients are in mg

Table No.2: Factor Combination as per the Chosen Experimental Design-

Evaluation Parameters:

• Physical Appearance: Visual inspection for color, shape, and texture.
• Weight Variation and Drug Content: Assessed as per pharmacopeial methods.
• Disintegration Time: Measured using a standard disintegration test apparatus.
• In Vitro Drug Release: Conducted using USP Type I apparatus in phosphate buffer (pH 6.8).
• FTIR and DSC Analysis: Performed to check drug-excipient compatibility.
• Stability Study: The optimized formulation was stored under accelerated conditions and evaluated periodically.

RESULTS AND DISCUSSION:

The physical characteristics of the prepared suppositories were within acceptable limits. FTIR and DSC analyses confirmed that there were no significant interactions between Naproxen and PEG bases. Drug content was found to be uniform across all formulations. Disintegration time varied with PEG ratios. Suppositories with higher PEG 400 content showed faster disintegration but slower drug release due to lower molecular weight. In contrast, increasing PEG 4000 delayed disintegration but enhanced sustained release. The optimized formulation balanced these effects, providing rapid disintegration (within 6 minutes) and over 85% drug release within 60 minutes. Response surface methodology indicated a significant effect of PEG 4000 concentration on disintegration time and drug release. The optimized batch showed good stability over three months under accelerated conditions.

Evaluation Parameter of Optimized Formulation of Naproxen Rectal Suppositories

Color Appearance & Surface texture for Optimized Formulation

Table No.3: Color Appearance & Surface texture for Optimized Formulation

Evaluation of Batches of Naproxen Suppositories Generated by CCD (NPXs1-NPXs10)

Table No. 4: Evaluation of Batches of Naproxen Suppositories Generated by CCD:

Drug Released of Batches Generated by CCD

Table No. 5: Drug Released of Batches Generated by CCD:

Fig No.3: In-vitro Drug Release Profile of Naproxen Optimized Batches

Data Analysis:

• Dissolution (Y1):

Following regression equation could describe the dissolution response,

Dissolution (Y1) = + 90.85 + 2.12X1 + 1.15X2

Concerning Dissolution, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a positive sign. Positive sign of X1 and X2 indicate that direct relationship with response Y1 (Dissolution%). It reveals that conc. of PEG4000 and PEG400 shows positive effect on dissolution. As the conc of both X1 and X2 increases with increase in response Y1 (%DR). ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (p=0.0032 for X1, p=o.0125 for X2).

• Disintegration Time (Y2):

Following regression equation could describe the melting point response,

Disintegration Time (Y2) = + 8.45 - 0.095X1 - 0.73X2

Concerning Disintegration, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. The negative sign of X1 and X2 indicate an inverse relationship with response Y2(Disintegration Time). It reveals that the concentration of PEG4000 and PEG 400 shows a reducing effect on disintegration time. As the concentration of both X1 and X2 increases,the response Y2 (Disintegration Time) decreases,which is desirable for faster suppository disintegration. ANOVA was used to identify the significant effect.The result was found to be significant at that level of probability (p=0.0045)

Graphical Representation:

A)        For %Drug Released-

Fig. No. 4: Response Surface Contour Graph Showing the Influence of Conc. PEG400 (X1) and Conc.PEG4000 (X2) on %DR(Y1)

Fig No. 5:  3D Response Surface Graph Showing the Influence of Conc. of PEG 400 (X1) and Conc. of PEG 4000 (X2) on % DR (Y1)

B)        Disintegration Time:

Fig No.6: Response Surface Contour Graph Showing the Influence of Conc. of PEG400(X1)Conc. of PEG4000 (X2) on Disintegration time (Y2)

Fig No.7;  3D Response Surface Graph Showing the Influence of Conc. of PEG400(X1) and Conc. of PEG4000 (X2) on the Disintegration (Y2)

Stability test:

Short Term Stability Study for Optimised Batch (NPXs7)

Stability study of Naproxen Suppository evaluated for period of one month and was found to be stable at room temperature (37°C±0.50C) and refrigeration temperature (2°C-8°C). Hence, there was no significant change found in physical appearance. No degradation was observed in both cases and formulation testing parameters like hardness, melting point and percentage drug released were found to be within ±5%.

Table No.6: Stability Study of Optimized Batch (NPXs7) of Naproxen Suppository