Formulation and Evaluation of Captopril Loaded Mouth Dissolving Films for Rapid Antihypertensive Action

Oral route of drug administration is a most preferred route. Due to its ease of administration, non-invasiveness, Adaptability, patient compliance and acceptability. Many alternatives to the oral route of drug delivery have consistently been introduced employing new and innovative technology for nauseated patients, elderly patients, and children. And patients who do not comply. Technological advancements have led to the introduction of bio adhesive mucosal dosage forms, such as adhesive tablets, gels, and patches. The use of polymeric films to deliver medication into the buccal cavity has shown a lot of promise among different dose forms in the recent past, when applied on the tongue, oral disintegrating films (ODFs) instantly hydrate by absorbing saliva after dissolving and/or disintegrating, releasing active ingredients. Medication from the dose container, ODFs are a type of formulation that is frequently made using hydrophilic polymers that allow for quick dissolving upon Coming into touch with saliva. The most common types of oral disintegrating drug delivery methods are oral disintegrating tablets (ODTs) and oral disintegrating films (ODFs). The most common types of oral disintegrating drug delivery methods are oral disintegrating tablets (ODTs) and oral disintegrating films (ODFs). These systems were created in late 1970 as a substitute for traditional dosage forms, such as rapidly dissolving Capsules and pills for children and elderly patients having trouble swallowing standard dose forms.  An ODF is the size of a postage stamp. When ODF as introduced to the market, it was highly connected to patient counselling regarding the proper Administration by providing guidance such as “do not chew/do not swallow. However, in spite of these instructions, incidents regarding chewing and swallowing were often reported. But ODFs untied the masses from these adverse events. Mouth Dissolving Films (MDFs) is an innovative and impressive drug delivery system which increases patient compliance. MDFs deliver the drug systematically via sublingual or buccal route of administration and additionally for local action1. MDFs constitute a thin film which when positioned on the tongue gets wet by saliva and moistens rapidly and then film dissolves and disintegrates within seconds to supply the drug for absorption. When compared to capsules and different dosage forms, MDFs are advantageous because film dissolves within seconds and shows onset of action. MDFs increases bioavailability, shortens the onset of time, prevents first pass metabolism. Fast dissolving drug delivery is the maximum advanced form as it improves efficacy of drug, flexibility, disintegration and dissolution. Special future of mouth dissolving Films: 

• Elegant thin film.
• Unconstructive.
• It comes in various shapes and sizes.
• Rapid disintegration. 
• Rapid onset of action.
• Provide a pleasant mouth feel. 
• Have a pleasant taste. 

Advantages 

Fast dissolving oral Films being an advanced evolution of fast dissolving drug delivery systems have some outstanding advantages over conventional dosage form and orally disintegrating tablets they are.

1. It is easy to administer to children, the elderly, and mental illness patients who have difficulty swallowing tablets and other solid dose forms.
2. No water is required for swallowing.
3. Fast-acting drugs that dissolve and absorb rapidly yet are not very soluble in water.
4. By reducing adverse effects and increasing bioavailability at lower dosages, pregastric absorption can result in better clinical performance.
5. It is possible for bitter drugs to hide their flavour.
6. Helpful in circumstances that call for quick action, such motion sickness, an unanticipated allergic reaction, or coughing.
7. Fit, hypertension, bronchitis, or asthma.
8. More economical, the dosage process is easy to follow and accurate, affordable transit.
9. Superior clarity and consistency in thickness compared to extrusion.
10. The wide surface area allows for rapid disintegration and dissolution in the oral cavity.
11. Its dosages didn’t require water to be administered. 
12. There is no chance of choking.
13. Ophthalmic thin films can be used to deliver drugs to the eye.

Disadvantages

1. Uniformity of dose is a technological problem.
2. They are hygroscopic.
3. It is not possible to include high dose (<40 mg/4 cm2 piece).

1.2 Biopharmaceutical Classification System     

The Biopharmaceutics Classification System or BCS is a system which classifies bioactive molecules based on solubility and permeability which is widely used to guide new drug development and drug formulation, as well as predict pharmacokinetics under prescribed conditions. Established by Gordon Amidon etc. All the original purpose of the system was to aid in the regulation of post-approval changes and generics, providing approvals based solely on in vitro data when appropriate. Importantly, since the majority of drugs are orally dosed, the system was designed around oral drug delivery via passive diffusion process through the small intestine where   major extent of oral absorption is largely influenced by drug’s membrane permeability and solubility. Currently it is used to predict the bioavailability of the drug, used in in-vivo & in vitro correlations and bioavailability studies.

Table No.1: Biopharmaceutical Classification system

According to the Biopharmaceutical Classification System (BCS) drug substances/APIs are classified to four classes Upon Their High/Low Solubility and Permeability:

Class I Drugs

The drugs belonging to BCS class 1 are highly soluble and highly permeable, so they can be formulated as a suitable conventional dosage forms. Well absorbed orally. They exhibit a high absorption number and a high dissolution number they do not have solubility nor permeability limitation therefore they generally represent a low risk group of compounds in terms of the potential for excipients to affect absorption, compared to other BCS classes

? Example:  Captopril, Metoprolol, Paracetamol

These compounds are well absorbed, and their absorption rate is usually higher than excretion.

Mouth-Dissolving Film’s Composition

To prepare Mouth Dissolving Film we need, API which should be in concentration range between 1-25%, Plasticizer in concentration range between 0-20%, flavoring agent in concentration between 2-10%, Sweetening agents in concentration between 3-6%, hydrophilic polymer/film former in concentration between 40-50%, saliva stimulation agent in concentration between 2-6%, colour 01%, surface active agent used as Quantity sufficient.

Hydrophilic Polymer/Film Former

The breakdown time of a movie is greatly influenced by the properties of polymers. Hydroxypropyl Methylcellulose, methylcellulose, pullulan, carboxymethyl cellulose, polyvinylpyrrolidone, etc. are a few Examples of frequently used water-soluble polymers/film formers. Polymerized resin is one example of a Novel film-forming substance

Plasticizer

This stops the membrane from rupturing. It must get along with the other ingredients. Several excipients, including castor oil, phthalates, polyethylene glycol, and phthalates.

Sweetening Agent

Mouth-melting films need to taste good in order to be accepted and appreciated by patients because they must be consumed dry and without water in order to dissolve and disintegrate in the oral cavity. Sucrose, Fructose, aspartame, sorbitol, acesulfame-K, and sucralose are some examples of sweeteners.

Saliva Stimulating Agent

These are helpful in increasing saliva production in the mouth, which promotes quick breakdown. Acids like Tartaric, lactic, malic, ascorbic, and citric are used as examples.

Flavouring Agent

Common Flavors include citrus, vanilla, coffee, cocoa, and chocolate.

Surfactant

They function as wetting, dispersing, or dissolving agents. Poloxamer, sodium lauryl sulfate, and minor are a Few examples.  Surfactants are used to make poorly soluble medications more soluble as well as to Moisten, disperse, and solubilize the membrane and make it easier to release the active ingredients Benzethonium chloride and cadence are other few examples.

AIM AND OBJECTIVES:

5. AIM: 

To develop a novel drug delivery system in the form of mouth-dissolving films (MDFs) that enhances patient compliance by providing a convenient, fast-dissolving, and effective alternative to conventional dosage forms such as tablets and capsules.

5. Objectives:

1. Improved patient compliance:

Provide an alternative for individuals who have difficulty swallowing pills (e.g., pediatric, geriatric, and dysphagic patients).

2. Rapid drug action:

Ensure fast onset of action by delivering the drug through the oral mucosa, bypassing the gastrointestinal tract and first-pass metabolism.

3. Ease of administration:

Offer a non-invasive, easy-to-use system without the need for water or additional aids, making it suitable for on-the-go use.

4. Enhanced bioavailability:

Increase drug bioavailability by leveraging absorption through the buccal or sublingual route.

5. Reduced dosing frequency:

Achieve effective therapeutic outcomes with potentially lower doses due to enhanced bioavailability and rapid onset.

6. Cost-effective manufacturing:

Develop formulations that are simple to manufacture, scalable, and cost-effective for mass production.

7. Compatibility with various drugs:

Adapt the formulation to accommodate drugs with different solubility profiles and improve stability.

8. Minimized side effects:

Reduce systemic side effects by targeting local or systemic delivery through controlled drug release.

METHODS OF PREPARATION:

1. Solvent casting method: 

It is very old film making method. This technique involves dissolving or suspending the medication in a solution that contains plasticisers, polymers, and other excipients dissolved in a volatile solvent, such as water or ethanol. Known as “film dope,” it is subsequently cast in a petri plate and dried in an oven or other drying apparatus to eliminate all volatile solvents. After drying, the film is die-cut into strips and placed within airtight pouches. Because the temperature required to remove the volatile solvents is lower than with the hot melt extrusion approach, this technique works well for films that include heat-sensitive drugs or API.

Benefits 

• Compared to the extrusion process, the film has better clarity and thickness consistency.
• It also has a fine sheen and no die lines. 
• This process creates films with improved physical qualities and more flexibility.

Figure No.01: solvent casting method

Experimental Section:

Drug profile:   Captopril

Figure no 2:  structure of captopril

Molecular formula: C9H15NO3  

Chemical Name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid. 

Drug class: Captopril is in a class of medications called angiotensin-converting enzyme (ACE) inhibitors. It decreases certain chemicals that tighten the blood vessels, so blood flows more smoothly and the heart can pump blood more efficiently.                                                 

Figure N0 3: Api Of Captopril

Solubility: Captopril is highly soluble in water (around 160 mg/mL) and other solvents like methanol and ethanol, but sparingly soluble in chloroform and ethyl acetate.

Mechanism of Action: Like all other ACE inhibitors, captopril blocks conversion of angiotensin I to the potent vasoconstrictor angiotensin II and inactivates simultaneously the vasodilator peptide bradykinin. Besides its blood pressure-lowering properties, captopril has various immunomodulatory functions.

Indications: 

FDA-Approved Indications

• Hypertension

Initial therapy for patients with normal renal function.

In patients with impaired renal function, captopril should be reserved for those patients who have developed unacceptable side effects or failed to respond to other drug therapy. Effective alone and in combination with other antihypertensive agents.

• Heart Failure

According to AHA/ACC/HFSA 2022 guidelines, captopril is indicated for managing HFREF (heart failure with reduced ejection fraction). ACE inhibitors, including captopril, are included in goaldirected medical therapy (GDMT), with an established reduced risk of rehospitalization and improved survival.

• Left Ventricular Dysfunction After Myocardial Infarction

Captopril improves survival following myocardial infarction in clinically stable patients with a left ventricular ejection fraction of less than 40% and reduces the incidence of hospitalization. Captopril prevents remodelling and reduces cardiovascular mortality in patients with heart failure.

•  Diabetic Nephropathy

Diabetic nephropathy is the leading cause of end-stage kidney disease (ESKD) in developed countries. This condition is due to microvascular complications of diabetes and can occur in type 1 and type 2 diabetes. Early treatment can prevent or slow the onset of diabetic nephropathy.

Root of Administration:

Adult Dosage

Captopril should be taken 1 hour before meals. Therapy initiation requires analysis of recent antihypertensive drug treatment, the extent of blood pressure elevation, and salt restriction. If possible, the previous antihypertensive drug regimen should be stopped 1 week before starting captopril. The daily dose of captopril may be increased every 24 hours under continuous medical supervision. The initial daily dosage should be reduced for patients with significant renal impairment, and smaller increments should be utilized for titration. 

• Hypertension

Initial dosage: 25 mg, 2 times or 3 times per day Unsatisfactory reduction of blood pressure after 1 to 2 weeks: Increase the dosage to 50 mg, 2 or 3 times daily. The dosage of captopril may increase to 100 mg, 2 or 3 times daily, and to 150 mg, 2 or 3 times daily, if further blood pressure reduction is required.  The usual dosage range is 25 to 150 mg, 2 or 3 times daily. The maximum daily dose should not exceed 450 mg.

• Heart Failure

The initial dosage in patients vigorously treated with diuretics, hyponatremic, and hypovolemic patients is 6.25 or 12.5 mg, 3 times daily with titration to the usual daily dosage within several days. According to AHA/ACC/HFSA guidelines, the initial dosage in patients is 6.25 mg, 3 times daily, and the target dosage is 50 mg, 3 times daily. After a dosage of 50 mg, 3 times daily, further increases in dosage should be delayed for at least 2 weeks.

• Left Ventricular Dysfunction after Myocardial Infarction

After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg, 3 times daily, and then increased to 25 mg, 3 times daily, over several days. Long-term use: target maintenance dose of 50 mg, 3 times daily. Therapy can be initiated as early as 3 days following myocardial infarction.

• Diabetic Nephropathy

Long-term use: 25 mg, 3 times daily 

• Acute Hypertensive Crisis

Dosed orally or sublingually: 25 mg. Alternative therapy should be considered if blood pressure is nonresponsive within 20 to 30 minutes.

• Raynaud Phenomenon

The initial dosage is 12.5 mg, 2 times daily; it can gradually increase to 25 mg, 3 times daily. The starting dosage may gradually increase to 25 mg, 3 times daily. Neutropenia is a common adverse event with captopril administration in patients with the Raynaud phenomenon.

Pharmacokinetics:

Absorption: Captopril is well-absorbed orally, with peak plasma concentration achieved within approximately 1 hour of administration. Food decreases the bioavailability of captopril; captopril should be administered 1 hour before meals.

Distribution: The volume of distribution is 0.8 L/kg. Plasma protein binding is approximately 25% to 30%. Captopril can cross the blood-brain barrier.

Metabolism: Captopril is metabolized to cysteine-captopril disulfide and captopril dimer disulfide.

Elimination: The kidney is the major route of elimination of captopril. The clearance is 0.7 L/h/kg, and the elimination half-life is approximately 2 hours; thrice daily administration is required. The clearance of captopril (unchanged) is greater than the glomerular filtration rate due to the active tubular secretion

Adverse effect: Dry cough (1% to 10%) 

Proteinuria (1%), which subsides or clears within 6 months even when captopril therapy is continued 

Renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency (0.1% to 0.2%) Neutropenia (<1000/mm3) or agranulocytosis with myeloid hypoplasia Rash with pruritus and occasionally with fever, arthralgia, and eosinophilia (4% to 7%)  Angina pectoris, myocardial infarction, Raynaud syndrome, and congestive heart failure (0.2% to 0.3%)  Dysgeusia (diminution or loss of taste perception) is reversible and usually self-limited (2% to 4%)  Anaphylactoid and other related reactions due to the inhibition of the metabolism of eicosanoids and polypeptides, including bradykinin Intestinal angioedema, which presents as abdominal pain with or without nausea or vomiting  Flushing or pallor  Tachycardia, chest pain, and palpitations, Hypotension 

Contraindications: 

Hypersensitivity to captopril, any component of the formulation, or any other ACEI. Angioedema related to previous treatment with ACEI. Concomitant aliskiren use in patients with diabetes Coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (sacubitril) 

Drug interaction: Sacubitril. …

High blood pressure drugs. …

Diuretics (water pills) …

Potassium supplements and potassium-based salts. …

Mood stabilizers. …

Pain drugs. …

Drugs to prevent organ transplant rejection. … Gold.  

Special consideration: Captopril should be taken 1 hour before meals. Therapy initiation requires analysis of recent antihypertensive drug treatment, the extent of blood pressure elevation, and salt restriction. If possible, the previous antihypertensive drug regimen should be stopped 1 week before starting captopril.

Melting point: 103°c

Boiling point: 108°c

Pka: Captopril has two Pka values: 3.7 and 9.8

Stability: As a solid, captopril is stable; however, in solution, it undergoes free-radical oxidation to yield captopril disulfide as the major degradation product. This degradation is complex and concentration and pH dependent, with the highest stability at pH 3.5.

 Carriers:

 Polymer Profile 

Table No 2: HPMC E15

MATERIAL AND METHOD

Formula development

Captopril Mouth Dissolving Film – Formula [ per 10 films]

Table No. 3. formula of mouth dissolving film

4.4 Preparation of mouth dissolving film

1. Polymer Solution Preparation

Description: Hydroxypropyl methylcellulose (HPMC E15) is dissolved in distilled water and allowed to swell.

Visual: A clear, viscous solution in a beaker, often stirred using a magnetic stirrer.

2. Addition of Plasticizer and Excipients

Description: Polyethylene glycol 400 (PEG 400), citric acid, sweeteners and flavouring agents are added to the polymer solution with continuous stirring

Visual: The solution remains clear, with all components uniformly mixed.

3. Incorporation of Captopril

Description: Captopril is added to the solution and stirred until completely dissolved.

Visual: A homogeneous solution, ensuring even distribution of the drug.

4. Casting the Film

Description: The final solution is poured onto a flat, levelled surface (like a glass plate) and spread uniformly using a film applicator.

Visual: A wet, uniform layer of solution spread over the casting surface.

5. Drying the Film

Description: The cast film is dried at 40°C in a hot air oven until the solvent evaporates completely.

Visual: A dry, transparent film formed on the casting surface.

6. Cutting and Packaging

Description: The dried film is carefully peeled off and cut into desired sizes (e.g., 2x2 cm squares), each containing a specific dose of Captopril.

Visual: Uniformly cut film strips, ready for packaging.

Fig no.4 Mouth Dissolving Film Contaning Captopril

Figure.no.5.   Dry mouth dissolving films of captopril

RESULTS AND DISCUSSION:

The films were uniform, smooth, and transparent. Evaluation results are summarized below:

Evaluation Parameters and Results:

Table No. 4. Evaluation Parameters and Results