Development & Evaluation Of Polyherbal Granules Filled Hard Gelatin Capsules Containing Ciltoria Ternatea & Vitex Agnus Castus For Menopausal Symptom Management

Fig 1: Menopause symptoms

Hormone Replacement Therapy (HRT) is commonly used to manage menopausal symptoms. However, long-term use of HRT may lead to side effects such as increased risk of cardiovascular diseases and breast cancer. Therefore, there is a growing interest in combining synthetic drugs with herbal ingredients for safer and more effective therapy. Tibolone is widely used for managing menopausal symptoms due to its estrogenic, progestogenic, & androgenic activity. It helps in relieving vasomotor symptoms and prevents bone loss. ^[1]

1.1.1. Prevalence of Menopause

Menopause is a natural biological process characterized by the permanent cessation of menstruation due to the loss of ovarian follicular activity. It generally occurs between the ages of 45 and 55 years, with the average age being approximately 50 years worldwide. In India, menopause commonly occurs slightly earlier, around.

46–48 years of age. The prevalence of menopause is increasing globally because of improved life expectancy and better healthcare facilities. According to epidemiological studies, millions of women enter menopause every year, and postmenopausal women constitute a significant proportion of the female population worldwide.^[2] It is estimated that women spend nearly one-third of their lives in the postmenopausal phase. Various menopausal symptoms are highly prevalent among women, including hot flashes, night sweats, mood changes, sleep disturbances, osteoporosis, and cardiovascular complications. The prevalence and severity of menopausal symptoms vary depending on genetic, environmental, nutritional, and socioeconomic factors. Vasomotor symptoms such as hot flashes are reported in nearly 50–80% of menopausal women. Osteoporosis and cardiovascular diseases are also more common after menopause due to oestrogen deficiency. Increasing awareness regarding menopause and its management is important because the growing population of postmenopausal women represents a major public health concern.^[3,4,5]

1.1.2 Causes of Menopause^[6,7]

Menopause occurs mainly due to the natural decline in ovarian function and depletion of ovarian follicles with advancing age. As the ovaries lose their ability to produce oestrogen and progesterone hormones, menstrual cycles gradually become irregular and eventually cease permanently. The causes of menopause can be classified into natural, premature, surgical, and induced menopause.

i. Natural Menopause

Natural menopause occurs as a part of the normal aging process in women, usually between 45–55 years of age. It results from gradual depletion of ovarian follicles and reduced secretion of estrogen and progesterone hormones.

ii. Premature Menopause

Premature menopause occurs before the age of 40 years. It may be caused by:

• Genetic abnormalities
• Autoimmune disorders
• Ovarian failure
• Severe infections
• Metabolic disorders

iii. Surgical Menopause

Surgical menopause occurs due to surgical removal of both ovaries (bilateral oophorectomy). It may also occur after hysterectomy if ovarian blood supply is affected. Symptoms are usually sudden and more severe because hormone levels decline abruptly.

iv. Induced Menopause

Induced menopause may occur due to:

• Chemotherapy
• Radiotherapy
• Anticancer drugs
• Certain hormonal treatments

These treatments damage ovarian tissue and reduce hormone production.

v. Lifestyle and Environmental Factors

Certain factors may contribute to early menopause, including:

• Smoking
• Poor nutrition
• Stress
• Low body weight

Thus, menopause is mainly associated with hormonal changes resulting from ovarian aging or damage to ovarian function.

1.1.3 Treatment of Menopause

The treatment of menopause mainly aims to relieve menopausal symptoms, improve quality of life, and prevent long-term complications such as osteoporosis and cardiovascular diseases. Treatment depends on the severity of symptoms, age of the patient, and overall health condition.

a. Hormone Replacement Therapy (HRT)^[1,3]

Hormone Replacement Therapy is the most effective treatment for menopausal symptoms caused by estrogen deficiency.

Types of HRT

• Estrogen therapy
• Combined estrogen and progesterone therapy

Routes of Administration

• Oral tablets/capsules
• Transdermal patches
• Vaginal creams and rings
• Injectable preparations

Adverse Effects

• Nausea
• Breast tenderness
• Headache
• Risk of thromboembolism
• Increased risk of certain cancers with prolonged use

b. Non-Hormonal Therapy^[8,9,10]

Non-hormonal drugs are used in women who cannot receive hormone therapy.

Drugs Used

• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Selective Norepinephrine Reuptake Inhibitors (SNRIs)
• Gabapentin
• Clonidine

These drugs help reduce vasomotor symptoms such as hot flashes.

c. Lifestyle Modifications

Lifestyle changes play an important role in menopause management.

Recommended Measures

• Regular physical exercise
• Healthy balanced diet
• Adequate calcium and vitamin D intake
• Smoking cessation
• Reduction of alcohol and caffeine intake
• Stress management and yoga

d. Alternative and Supportive Therapy

Some women use supportive therapies for symptom relief:

• Phytoestrogens
• Herbal supplements
• Cognitive behavioural therapy
• Relaxation techniques

Thus, appropriate treatment and lifestyle management can effectively reduce menopausal symptoms and improve overall health in postmenopausal women.

1.2 Oral Drug Delivery System

Oral drug delivery system is the most commonly used method for administration of drugs through the oral route to achieve systemic or local therapeutic effects. In this system, the drug is administered by mouth and absorbed through the gastrointestinal tract. Oral dosage forms include tablets, capsules, syrups, suspensions, powders, and solutions. The oral route is widely preferred because it is convenient, non-invasive, economical, and provides better patient compliance compared to other routes of administration.

1.2.1 Capsules

Capsules are solid unit dosage forms in which the drug substance is enclosed within a hard or soft soluble shell made mainly of gelatin or other suitable polymers. Capsules are one of the most widely used oral drug delivery systems because they are easy to swallow, provide accurate dosing, and improve patient compliance. The capsule shell dissolves in the gastrointestinal fluids after administration, releasing the medicament for absorption. Capsules can contain powders, granules, pellets, semi-solids, or liquid formulations depending on the type of capsule used.

1.2.2 Tablet vs Capsule

Table no 1: Tablet vs Capsule

2. DRUG PROFILE

i. BUTTERFLY PEA^[11-16]

Fig 2.1: Blue pea flower

Synonym: Aparajita, Blue pea, Darwin pea, Asian pigeonwings

Biological source: The biological source of the butterfly pea flower is Clitoria ternatea L., a perennial herbaceous plant. 

Family: Fabaceae (subfamily Faboideae).

Chemical constituents:

Fig 2.2: Chemical constituents of blue pea

Polyphenolic compounds like kaempferol, anthocyanins, phenolic acid, myricetin, and quercetin are abundant in it. Butterfly pea flowers also include lipophilic components, such as fatty acids like palmitic acid, linolic acid, and arachidic acid; phytosterols like campesterol, sitostanol, and sigmasterol.

Solubility: Highly soluble in water, soluble in polar solvents & insoluble in non- polar solvents.

Pharmacological Profile: Blue pea's antioxidant, neuroprotective, anti-inflammatory, and modest adaptogenic qualities may be beneficial during menopause. Its anthocyanins, flavonoids, and phenolic substances may aid with cognitive decline, anxiety, mood swings, fatigue, oxidative stress, and skin ageing. Its bioactive ingredients have low oral bioavailability due to gastrointestinal instability and significant first-pass metabolism, with metabolites being removed thru urine and bile. The plant predominantly functions thru non-hormonal mechanisms, such as free radical scavenging, cholinergic activity modulation, and potential stress response regulation, with no significant oestrogen receptor agonistic activity. It is generally well tolerated, but stomach problems, sleepiness, and moderate allergic responses may occur. It is normally avoided during pregnancy and lactation, and it should be used with caution when combined with CNS depressants or antihypertensive medications due to potential synergistic effects.

ii. CHASTEBERRY^[17-22]

Synonyms: Monk’s pepper

Biological source: The biological source of Vitex consists of the dried ripe fruits, and occasionally the leaves and flowering tops, of the plant Vitex agnus-castus.

Family: Lamiaceae (formerly classified under Verbenaceae).

Fig 2.3: Chasteberry plant & chasteberry seeds

Chemical constituents:

Fig 2.4: Chemical constituents of Vitex agnus-castus

Vitex agnus-castus has a wide variety of pharmacologically significant chemical constituents. Its dopaminergic activity is mainly caused by diterpenoids, which include rotundifuran and vitexilactone, among other major bioactive compounds. The plant also contains iridoid glycosides like aucubin and agnuside, flavonoids like casticin, kaempferol, and quercetagetin, and essential oils.

Solubility: Soluble in polar solvents, insoluble in non-polar & inert solvents

Pharmacological Profile: According to its endocrine-modulating and neuroendocrine properties, Vitex agnus-castus is used as a supportive herbal therapy for menopausal symptoms like mood swings, irritability, hot flashes, sleep disorders, and breast discomfort. Its diterpenoids, flavonoids, and iridoid glycosides mostly work by stimulating dopaminergic D₂ receptors, which lowers prolactin release and aids in controlling the balance of FSH, LH, and reproductive hormones. Its components undergo hepatic metabolism, conjugation, and excretion primarily thru urine and bile following oral dosing; nevertheless, comprehensive human pharmacokinetic data are scarce. Although chasteberry is usually well accepted, it can cause irregular menstruation, headaches, dizziness, or skin problems. It should be taken with caution in hormone-sensitive disorders, with dopamine-modulating medications or hormone replacement treatment, and during pregnancy and breastfeeding.

3. MATERIAL & METHODS

MATERIALS:

The active compounds in the mixture were ashwagandha, bamboo silica, chasteberry extract, and blue pea extract, which offered antioxidant, hormonal balance, adaptogenic, and bone-supporting qualities, respectively. Magnesium stearate, ethyl cellulose, microcrystalline cellulose, talc, and HPMC were utilised as lubricant, diluent, glidant, and binder/film forming, respectively. The extracts of blue peas and chasteberries were made in a lab, while the other ingredients were procured from SSJCOP Store and internet retailers.

METHODS:

EXTRACTION METHOD^[17,25,29]

Fig 3.1: Blue pea extract Fig 3.2: Chasteberry extract

Extraction method of Blue pea & Chasteberry

Dried powdered blue pea flowers and chasteberry seeds were taken

↓
Extracted with Ethanol: Water (70:30, v/v) individually

↓
Macerated for 24–72 h with intermittent shaking
 ↓
Filtration through muslin cloth & Whatmann filter paper

↓
Concentration of filtrate using a water bath
 ↓
Obtained concentrated extract

 ↓
Storage in an airtight container

FORMULATION DEVELOPMENT METHOD^[25,28,30]

Accurately weighed quantities of herbal extracts and excipients were mixed uniformly. Binder solution was added gradually with continuous mixing to obtain a coherent damp mass. The wet mass was passed through sieve no.12 to prepare wet granules. The prepared granules were dried in a tray dryer or hot air oven at controlled temperature until optimum moisture content was achieved. Dried granules were re-sieved to obtain uniform granule size. Finally, lubricants and glidants were added, mixed properly, and the prepared polyherbal granules were then filled into hard gelatin capsules manually. Capsules stored in airtight container.

Table no 3: Formulation table for composition of polyherbal granules

4. RESULT & DISCUSSION

Table no 4.1: Organoleptic evaluation of blue pea extract & chasteberry extract

Fig 4.1: Phytochemical evaluation of blue pea extract

Table no 4.2: Phytochemical evaluation of blue pea extract^[11-22]

Fig 4.2: Phytochemical evaluation of chasteberry extract

Table no 4.3: Phytochemical evaluation of chasteberry extract^[11-22]

Table no 4.4: Evaluation of Flow properties of granules ^[26,27,30]

Fig 4.3: Flow properties Evaluation

Fig 4.4: FTIR peak of Blue pea and Chasteberry

Table no 4.5: FTIR peak interpretation of drug sample^[25,30]

Formulation of granules

Fig 4.5: Granules & Capsules

5. Appearance Evaluation

Table no 4.6 : Appearance Evaluation of granules

5. Solubility test

Table no 4.7:  Solubility Study of granules in different medium

5. Weight Variation test

Table no 4.8: Weight Variation test

5. Content uniformity Test

Table no 4.9: Content uniformity Test

5. Moisture content Test

Table no 4.10: Moisture content test

5. Dissolution Test

Table no 4.11: Dissolution test^[28,30]

5. Disintegration Test

Table no 4.12: Disintegration Test^[28,30]

5. Antimicrobial test

Fig 4.6: Antimicrobial test

Table no 4.13: Antimicrobial test^[18,19]

5. Stability studies

Table no 4.14: Stability studies^[28,30]