The Cream which relieves the pain of Menstrual cramps without interfering with the Hormones or Period Cycle

 

Syeda Tuba Imam1*, Syed Saif Imam2

1Department of Obstetrics and Gynaecology JLNMCH Mayaganj, Bhagalpur, Bihar, India – 812001.

2Department of Pharmaceutical Sciences, HIMT College of Pharmacy, 8, Institutional Area,

Knowledge Park-1 Greater Noida (UP), India-201301.

*Corresponding Author E-mail: saifbehappy@gmail.com

 

ABSTRACT:

Dysmenorrhea is a disease caused by an overproduction of cytokines and prostaglandins throughout the menstrual cycle. NSAIDs are commonly used to relieve pain, but they can cause nausea, vomiting, hormonal imbalance, infertility, and irregularities in the menstrual cycle if used for a longer interval. Menthol, Cinnamaldehyde, Quercetin, and trans-anethole are combined in a novel Topical formulation that has significant anti-inflammatory and anti-dysmenorrheal activities with fewer side effects, and the excipients added improve the permeability rate and pharmacological action. The formulation quickly penetrates the stratum corneum and operates on the uterus’ endometrial lining cells, blocking pro-inflammatory cytokines including LPS, TNF, IL1, IL6, COX-2, LOX, oxidative stress, and lowering antioxidant levels. Menthol in the formulation has cooling and anti-spasmodic properties, making it effective in the treatment of dysmenorrhea-related nausea, vomiting, and diarrhoea. Anethol regulates excessive contractions via modifying Ca2+ and K+ channels. Cinnamaldehyde and Quercetin decrease inflammation by inhibiting the release of key cytokines and pro-inflammatory mediators. The yield value, sensory testing, spreadibility, dynamic viscosity, pH, anti-microbial preservative concentration, microbiological limit, sterlity testing, skin permeation test, and assay testing will all be used to evaluate the formulation. The O/W cream that has been developed will be far more effective than conventional NSAIDs, will be simple to apply, and will not disturb the menstrual cycle.

 

KEYWORDS: Cinnamaldehyde, Menthol, Quercetin, Trans-anethole, Dysmenorrhea, O/W cream, Anti-inflammatory.

 

 


INTRODUCTION: 

Dysmenorrhea is one of the most common problems that most women suffer at some point in their lives, and it has been ignored for generations. Synthetic drugs such as oral contraceptives and NSAIDs are available, but most women avoid them due to side effects such as changes in hormonal levels, impact on women's fertility after prolonged use, and disruption of the menstrual cycle. Females prefer to rather live in pain than take these medications.

 

 

 

Dysmenorrhea has a wide range of prevalence rates. Young women had a higher prevalence rate, with estimates ranging from 67% to 90% for those aged 17–24 years, in India lies between 60% - 79.67%1,2.

 

It is also known as painful periods or menstrual cramps, in simple words it is the pain that occurs during the menstruation of the follicular phase in the menstrual cycle. It begins around the time that menstruation begins and lasts up to the shedding of the endometrium is finally done (last up to 3-5 days in healthy women, in menorrhagia conditioned women it can last for more than a week). The pain is usually in the pelvis or lower abdomen and the other symptoms may include back pain, diarrhoea, vomiting, nausea, mood swings, fatigue, irritability, dizziness, and syncope.

 

Figure 1: Diagrammatic view of Dysmenorrhea

 

A survey reported that 36.6% of females suffer from moderate pain, 34.2% suffers from severe pain and 29.2% suffers from mild or no pain3. It is generally of two type’s primary and secondary, secondary dysmenorrhea is more likely to affect women during adulthood4,5.

 

Cause:

Dysmenorrhea is caused due to an increase in the intracellular calcium influx in uterine smooth muscle cells. This increase in Ca2+influx induces extracellular signal-regulated kinase (ERK1/2) and activates phosphor–myosin light chain 20 (p-MLC20), also there are an increase in prostaglandin F2α (PGF2α) levels which are induced due to an increase in the cyclooxygenase-2 (COX-2) levels. The increase of COX-2 is due to the increased oxidative stress, which causes pain in the uterine areas6.

 

 

Figure 2: Menthol

 

Menthol:

Menthol is an important phenolic compound of mint which is used because of its analgesic properties and anti-inflammatory potential. It possesses antiemetic, diaphoretic, carminative, anti-inflammatory, analgesic, emmenagogue, anti-spasmodic, and anti-catarrhal potential. It also has local anesthetic and counterirritant qualities7.

 

It reduces the levels of cytokines, declines the levels of the pro-inflammatory cytokines TNF-α and IL-6, and increases the level of the anti-inflammatory factor IL-108.

Mechanism of Action:

·       Transient receptor potential melastatin 8 (TRPM8) is a cold-activated cation channel expressed in a small subpopulation of peripheral sensory neurons. Menthol acts as a selective activator of TRPM8. Activation of “cold receptor” plays an important role in thermos-sensation and hence in pain sensation.

·       It raises the temperature threshold of the cold-sensing sodium- and calcium-channel TRPM8. Upon exposure, the channels become active at 27–31°C (instead of the normal trigger temperature, which is 5°C less) and promote the brain to give a sensation of cooling via the trigeminus nerve9.

·       It inhibits prostaglandin F2α and oxytocin and also myometrium contractile activity.

 

 

Figure 3: Diagrammatic representation of activation of TRPMS receptor of Menthol

 

Methanol has a principal component cyclic monoterpene which possesses the ability to block the calcium channel of intestinal smooth muscles it causes anti-spasmodic action and exerts relaxant effects on intestinal smooth muscle hence effective in Nausea, Vomiting, and Diarrhoea in dysmenorrhea10.

 

·       Menthol acts as an analgesic agent which blocks Voltage-gated Ca2+ channels (VGCCs) it inhibits spontaneous synaptic transmission and depolarization-induced Ca2+ influx, decreases excitability in cultured superficial dorsal horn neurons cause inactivation of channels and blockade of VGSC in the central nervous system, and mediate local anesthetic11.

·       Menthol produces its topical analgesic action through an interaction with the dense network of nerves that are embedded in the skin's dermal-epidermal junction.

 

Figure 4: Connamon aldehyde

 

Cinnamaldehyde:

Cinnamaldehyde is an active compound of Cinnamon which have numerous properties such as anti-inflammatory, anti-microbial, anti-fungal, anti-oxidant, anti-diabetic , anti-termites, nematicidal, mosquito larvicidal, insecticidal, anti-mycotic, and anti-cancer and also it is useful in dental problems (Halitosis, toothaches, and oral microbiota) and increases the blood circulation in the uterus12.

 

Mechanism of Action:

·       Cinnamaldehyde has the potential to stop the production of NO by inhibiting the iNOS13.

·       Cinnamaldehyde inhibits activation of transcription factor nuclear factor-kappa B (NF-κB).

·       It inhibits the secretion of cytokine interleukin-1β (IL-1β) which is a key mediator of the inflammatory response14.

·       It also obstructs the production of TNF alpha15.Cinnamaldehyde suppresses Interferon-gamma (IFN-γ), IL-6, IL-1α which is produced by LPS or lipoteichoic acid LTA16

·       Cinnamaldehyde also suppresses COX-2, MPAKs phosphorylation in the cells by reducing ERK, JNK, and p38 pathways.

 

Figure 5: Quercetin

 

Quercetin:

Quercetin is a flavonoid, mainly found in plants and foods like onions, berries, apples, Ginkgo biloba, St. John's wort, American elder, and in Buckwheat tea. Quercetin possesses anti-inflammatory, anti-cancer, anti-protozoal, anti-viral, ocular-protective, anti-microbial, cardio-protective, anti-arthritis potential and it also increases metabolic properties17-19. Quercetin also can inhibit platelet aggregation, lipid peroxidation, and capillary permeability, and stimulate mitochondrial biogenesis20.

 

Mechanism of Action:

·       Quercetin can inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) production in macrophages and LPS-induced IL-8 production21.

·       Quercetin possesses mast cell stabilizing properties. It also has an immunosuppressive effect on dendritic cells function22.

·       In glial cells, quercetin can inhibit LPS-induced mRNA levels of TNF-α and interleukin (IL)-1α, this effect of quercetin results in a diminishing apoptotic neuronal cell death which is induced by microglial activation. Quercetin also inhibits the production of COX-2 and lipoxygenase (LOX)23.

·       Quercetin inhibits Src- and Syk-mediated phosphatidylinositol-3-Kinase (PI3K)-(p85) tyrosine phosphorylation which further limits LPS-induced inflammation and also forms a complex with Toll-Like Receptor 4 (TLR4)/MyD88/PI3K which stops the activation of downstream signaling pathways24.

·       It inhibits pro-inflammatory cytokines mediated by FcεRI which are tryptase and histamine; this inhibition is due to inhibition of Ca2+ influx, as well as inhibition in phospho-protein kinase C (PKC).

·       Quercetin also acts against H2O2-induced inflammation by down-regulating the CD80 expression and vascular cell adhesion molecule 1 (VCAM-1)25.

·       Quercetin induces the production of Th-1 derived which is derived from interferon-γ (IFN-γ) and down-regulates Th-2 derived which is derived from interleukin 4 (IL-4).

·       Quercetin treatment with activated T cells shows blocking of IL-12-induced tyrosine phosphorylation of TYK2, JAK2, STAT3, and STAT4, resulting in a decrease in IL-12-induced T cell proliferation and Th1 differentiation26.

 

Figure 6: Trans – Anethole

 

Anethole:

Anethole is derived from Foeniculum vulgare Mill (fennel). Trans-anethole exhibits anti-cancer, anesthetic, anti-inflammatory, anti-genotoxic, anti-microbial, anti-viral, anti-thrombotic, and anti-oxidative potential. It has been experimentally proven that anethole has no toxic effects at low doses27. 

 

Mechanism of Action:

·       Trans-anethole can modify Ca2+ influx levels and Ca2+-activated K+ channels functions. This modification can be useful in inhibiting the extra contraction of the uterus28.

·       Anethole is a selective activator of TRPA1 Channels (which is responsible for the mediation of pain sensation). Activation of the TRPA1 channel causes relief in pain and also it produces a sense of cooling effect.

·       Trans-anethole also decreases the plasma levels of inflammatory cytokines IL-1β and IL-10 and pro-inflammatory cytokines IL-1729. Anethole also decreases the inflammatory mediators MMP-9 and NO.

·       Anethole also acts as an anti-inflammatory agent by suppressing the activation of NF-κB through blocking of IκB-α degradation. Anethole blocks the activation of the transcription factor AP-1, c-jun N-terminal kinase (JNK), and mitogen-activated protein kinase (MAPK-kinase) by suppressing TNF- α30.

·       Also, by inhibiting TNF- α, it suppresses both lipid peroxidation and reactive oxygen species31.

·       A higher concentration of anethole (more than 1mM) can completely inhibit H2O2-induced NF-κB activation.

 

MATERIALS AND METHOD:

Materials required:

Menthol crystals, Fennel seeds, Quercetin, Cinnamon barks, Shea butter, Extra virgin olive oil, Peppermint oil,

 

METHODOLOGY:

1.     Extraction of components:

(A)  Extraction of Trans Anethole from Fennel seeds:

Trans-anethole is extraction is done with supercritical CO2 together and ethanol as the modifier. Response surface methodology (RSM) is used to design the experiments and modeling. A gas chromatography-flame ionization detector (GC-FID) is used to analyze the fennel extract. The optimal conditions for extractions are 21.3 MPa and 21.55 MPa, 60.2°C and 55.59°C, 103 min and 96.38 min and 1.74 and 1.49ml/min of CO2 and the maximum extractions at these conditions are 56.38 w/w % and 55.50 w/w %32.

 

(B)  Extraction of Cinnamaldehyde from cinnamon:

The steam distillation process is used (the process is easy and cost-effective because of the difference in volatility between the essential oils and the other phase). The fresh bark of Cinnamomum cassia is crushed with the help of mortar and pestle and transferred in a steam distillation flask, distilled water is added and the system is heated. The condensed cloudy distillate (water plus essential oil) is transferred into a separating funnel. Then CH2Cl2 is added and shaken vigorously to separate layers. CH2Cl2 is added till the cloudy distillate is extracted out. The aqueous phase is discarded and the organic phase is retained back in the beaker. After this, anhydrous Na2SO4 is added to dry out the organic layer and then leave it for 10-15 mins. Finally, it is washed with CH2Cl2, and then with the help of gentle heating CH2Cl2 will be evaporated and cinnamaldehyde is extracted out33.

 

(C) Extraction of Quercetin from Onion:

The Azadirachta indica extract was sonicated for the duration of 20 min in sonicator and then passed through the ultra-membrane filter of pore size 0.45 μm. The quercetin and kaempferol were isolated and achieved by semi-preparative column Intersil ODS-3 C-18 (5 µm, 6 mm×250 mm), using mobile phase composition; acetonitrile: methanol: aqueous solution of 0.2% formic acid in a ratio of 60:10:30 at isocratic mode. The acceptable preparative separation achieved using 20 μl injection. The flow rate was set of 10 ml/min. Then by HPLC quercetin is separated out from kaempferol34.

 

2.     Preparation of Cream:

The cream will be prepared into two parts:

The first part will be the preparation of cream formulation from menthol crystals and quercetin and the second part is making cream formulation from essential oils which are cinnamaldehyde and trans-anethole.

 

Cream Production:

This cream is a blend of water and oil phases. It is oil and water emulsion. A formula for 250gm of cream of prepared by the following method:

·       Preparation of the oil phase:  Menthol crystals, shea butter, polo wax, Quercitin powder and Cetearyl alcohol are dispersed into olive oil. 

·       Oil phase consists: 20gm shea butter (wax), 6gm menthol crystals, 40ml of olive oil, 14gm of polo wax (emulsifying wax), 10.5gm of Cetearyl alcohol and 4.2gm quercetin.

·       Preparation of the aqueous phase:  the water-soluble ingredients are dissolved in aqueous phase glycerine in distilled water.

·       The aqueous phase consists of 121.5ml of distilled water, 20gm glycerine (humectant), 2.5gm Panthenol powder.

 

Procedure:

·       The oil phase will be prepared by melting the waxes, menthol, and Cetearyl alcohol at 150°C in olive oil on the hot water bath for about 20-25min. After preparation of the oil phase, the formulation is kept aside to reduce its temperature.

·       After, reduction in temperature to 80°C, it will be maintained for another 10 mins and quercetin will be added to the oil phase.

·       The aqueous phase will be prepared by dissolving 20gm of glycerine and 2.5gm of Panthenol powder in 121.5ml of distilled water. Then, the water phase is warmed to 75–80°C and stirred properly until all ingredients are dissolved properly. Weight is measured again if needed pre-heated distilled water is added to make up the volume.

·       After preparation of both aqueous and oil phases, the aqueous phase is slowly added to the oil phase and emulsified with the help of a Silverson emulsifier at 3400-3500rpm at 75°C and 165 bar pressure.

·       After emulsification, the formulation is left to cool down. When the temperature of the formulation is dropped to 40°C, essential oils like cinnamaldehyde (4.2ml), trans-anethole (4.2ml), and lavender (2-3 drops) are added and mixed thoroughly.

·       Then, the formulation is further cooled down to few more degrees. 1.875ml of euxyl k712 (Preservative), 0.525gm of glycol distearate (pH stabilizer), and 0.5ml of synthetic vitamin E are added with moderate agitation and continuous stirring.

·       In the last, the mixture will be stirred again for 15 min until the formulation became uniform a semisolid drug-loaded cream.

 

3.     Testing of Cream on different parameters:

(A) Calculation of yield values:

A spread meter is used to measure the flattening at a temperature of 25°C with a glass plate. Spread diameter is measured at different intervals of 5, 10, 30, 60, 120, and 180s. The yield value is calculated after 120 s with the following formula:

 

F = 47,040 × G × V/π2 × D5

 

Where; F: yield value (dynes/cm2), G: glass plate weight (g), V: sample size (cm3), D: diameter (mm) when sample spreading stopped

 

(B)  Sensory testing:

Sensory testing determines the irritability of the cream. Sensory testing was done using single blinding three samples prepared A B C

 

A: Menthol, quercetin, and essential oils are not present

B: Menthol, quercetin, and essential oils are present in half conc.

C: Menthol, quercetin, and essential oils were present as suggested

 

All the samples weighted 1gm each. Every tester washed their hands under running tap water and air dry for 5 min. All the testers were allowed to smell the aroma of three samples and will be allowed to rate them in a category 1-5 (where 1-poor, 2-somewhat poor, 3-somewhat good, 4-good, 5-excellent) on the assessment paper.

 

Testers are given 0.1 gm dollops of cream were gently rubbed on the abdominal area with their index finger in circular motion ten times. The cream was left on the body for 5 min and then the rating will be done by testers in the same assessment paper. Afterward, testers used tap water to rinse off the area where the cream has been applied. The same procedure was repeated for all the samples A B C. Testing is improved by asking testers to rate upon appearance and texture.

 

(C)  Spreadability test:

The cream base should spread easily without much force and not produce greater friction in the rubbing process. The spreadability test is calculated by using a spreadability apparatus which is made of a wooden board with a scale and two glass slides having two pans on both sides mounted on a pulley.

A sample is placed in between the two glass slides and 100 g weight is placed on the glass slide for 5 min to compress the sample to produce a uniform thickness. A weight of 250 g is added to the pan. The time required to separate the two slides is taken as a measurement of spreadability35.

 

S = m X l

         t

Where,

m – Weight tied on upper slide, l –   Length of glass slide, t –   Time in s

 

(D)  Measurement of dynamic viscosity:

The Dynamic viscosity of cream influences the efficiency of the process and also the satisfaction of the customer. Dynamic viscosity will be measured by using a type-E rotational viscometer. The viscosity is determined through the measurement of the torque.  The dynamic viscosity of 1 ml of cream is measured with a 1°34′ × R24 cone rotor at 1 rpm for 600 s at 25°C for 180 s. The reading is noted at different torque values till 100%35.

 

(E) pH:

Determination of pH is needed for irritability check. A dollop of cream is taken (about 10grams) and diluted to 50% with distilled water to get an accurate pH reading. Dip the pH meter in the diluted cream swirl it for one minute and note the reading.

 

(F)  Anti-microbial preservative concentration:

A known concentration of S. aureus, E. coli, P. aeruginosa, C. albicans, and A. Brasiliensis will be taken.  Strains of Microorganisms will be suspended in five tubes one strain in each, along with cream samples which are inoculated for 28 days at room temperature and determined for every 6 hours, 24 hours, 48 hours, 7 days, 14 days, and 28 days. The log reduction or percent reduction is calculated and compared to the acceptance criteria required by the method for acceptable preservation36.

 

(G) Microbial limit:

10g of prepared sample cream will be dispersed in 100 ml sterile tryptic soy broth in presence of 0.25% tween 80 and Shaken well for 15min at room temperature.

 

Microbial contamination is determined by spreading a thin layer of 0.5ml diluted prepared sample aseptically on nutrient and soybean-casein digest agar medium plates and incubate for 24-48h at 37°C isolates were purified and identified. A less than or equal to 1 × 103 CFU per gram or ml of the product is considered to be an acceptable value for topical applications37.

 

(H) Sterility Testing:

Prepare by diluting to about 1 ratio 10 in a sterile diluent such as peptone (1g/l). Transfer the diluted product to a medium; incubate the inoculated media for not less than 14 days. Observe the cultures several times during the incubation period. Shake cultures gently each day. The incubated culture was isolated and identified.

 

(I)   Skin permeation test:

A skin permeation test will be performed with the help of a Franz diffusion cell with a diffusion area of about 0.95cm2. The YMP (Yucatán Micro Pig, female) skin sample is mounted in the upper epidermal side of diffusion cells. The receptor cells will be filled with a solution prepared by dissolving 3% albumin in saline receiver phase and then, the receptor cells were kept at 32°C and stirred at a constant speed of 150rpm. The test is started with about 0.5g of each formulation applied to the skin. The sample was the YMP skin after 24 h and the receiver solution of 1, 3, 6, 9, 24 h after application. Samples were then deproteinized with methanol and then determined by HPLC after centrifugation (10 min 4 °C, 3600×g)38.

 

(J)  Assay Testing for Anti-inflammatory response:

In this Assay testing RAW264.7 cell line is prepared and tested for the presence of different types of LPS induced inflammatory cells. The murine macrophage RAW264.7 cell line will be maintained in DMEM (Dulbecco’s Modified Eagle Medium) supplemented with 10% heat-inactivated FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin and then determination of COX-2, iNOS, TNF-α, IL-1β, and IL-6 Genes by Quantitative Real-Time PCR (qRT-PCR)39.

 

Some other compounds such as Curcumin40, Catechins, Gallic acids41, Hesperidin42, EGCG43, Theaflavins44 etc. are also quite capable in lowering the inflammatory response in dysmenorrhea.

 

RESULT:

A formulation is prepared to treat dysmenorrhoea pain by mixing Quercetin, Menthol Cinnamaldehyde, and Trans-anethole in excipients like polo-wax, glycerine, shea butter preservatives, and pH stabilizers. The cream is prepared by preparing oil and water phases individually and then mixing it with the help of emulsifiers. After preparation, the cream will be tested on several factors such as yield value, sensory testing, spreadability test, dynamic viscosity, pH, anti-microbial preservative conc., microbial limits, sterility testing, skin permeability tests, anti-inflammatory testing assay testing on RAW264.7 cell line to check its bio-availability, stability of the formulation, irritability on skin, content uniformity of cream, and efficient working of cream.

CONCLUSION:

Dysmenorrhea is a problem through which every single girl is suffering or suffered once in their lifetime. Accumulation of pro-inflammatory cytokines, chemokines, ROS, MMPs, COX-2, and prostaglandins in the endometrium causes inflammation which leads to pain.

 

Menthol is a potent analgesic and anti-inflammatory compound which produces a cooling sensation by binds to TRPM8 receptors. Its anti-spasmodic action is effective in dysmenorrheal -induced Nausea, Vomiting, and Diarrhoea. Cinnamaldehyde inhibits cytokine interleukin-1β (IL-1β), iNOS, NF-κB,and supresses COX-2. Quercetin inhibits LPS-induced IL-8, TNF-α, IL-12-induced T cell proliferation, and reduces H2O2 induced inflammation. Anethole modifies Ca2+ influx which controls uterine contractions, activatesTRPA1 channel, and blocks JNK and MAPK-kinase.

 

ARFA drug is a stable o/w formulation in which menthol, cinnamaldehyde, Quercetin, and anethole are mixed along with shea butter, glycerine, polowax, Panthenol, Cetearyl alcohol, euxyl k712, Glycol distearate, and synthetic vitamin E. Shea butter helps in better spreadability of formulation and an excellent emollient. Glycerine provides a medium to dissolve water-insoluble Quercetin, polowax an emulsifier, Cetearyl alcohol helps prevent creams from separating into oil and liquid euxyl k712 is preservative and glycol-distearate as a pH stabilizer.

 

When the drug penetrates topical and uterine membranes and reaches the endometrium layer; where it acts by lowering the levels of prostaglandin, other pro-inflammatory cytokines, iNOS, and COX-2 and also produces a cooling effect (TRPM8), which reduces the pain and produces a sense of well-being. The chances of accumulation and toxicity of APIs are very low. The cream shows no physiological and psychological side effects.

 

The direction of usage: ARFA is only recommended in menstrual pain. Not recommended during normal abdominal pain, stomach allergies, or as a mood uplifter.

 

ACKNOWLEDGMENT:

The authors are thankful to the Department of Pharmacy, HIMT College, Greater Noida for providing kind guidance and excellent opportunity as well as necessary facilities for the research.

 

CONFLICTS OF INTEREST:

The authors confirm that the content of the article has no conflict of interest.

 

AUTHOR’S CONTRIBUTION:

Both the authors Dr. Syeda Tuba Imam and Syed Saif Imam have contributed equally to the paper. But, idea proposed by Dr. Syeda Tuba Imam.

 

DATA AVAILABILITY:

The original data that support the findings of this study are included in the article.

 

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Received on 07.11.2021             Modified on 14.05.2022

Accepted on 20.08.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(3):1239-1246.

DOI: 10.52711/0974-360X.2023.00205