Plant-derived preparation for rapid pain relief and method for preparing same

Abstract

Plant-derived preparation for rapid pain relief and method for preparing same The present invention relates to a plant-based formulation for rapid pain relief and a method for preparing said pain relief formulation. The plant-based formulation is made from solid turmeric extract and solid boswellia extract loaded in oil having a hydrophilic lipophilic balance value in the range of 10 to 19. Administration of said pain relief and anti-inflammatory formulation speeds up the pain relief process in subjects experiencing acute musculoskeletal pain.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a fast acting analgesic plant-derived formulation and a method for preparing said analgesic formulation, more particularly to a musculoskeletal analgesic plant-derived formulation prepared from solid turmeric extract and solid boswellia extract combined with oil having a hydrophilic lipophilic balance value of 10 to 19. Administration of said analgesic and anti-inflammatory formulation speeds up the analgesic process in subjects experiencing acute musculoskeletal pain. [Background technology]

[0002] 2. Background of the Invention Musculoskeletal pain refers to pain in muscles, bones, ligaments, tendons, and nerves. It may affect only one area of ​​the body, such as the legs. It may affect the whole body if you have a widespread condition, such as fibromyalgia. There are two types of musculoskeletal pain: chronic and acute. Acute musculoskeletal pain is sudden pain in the muscles, bones (including joints), tendons, ligaments, or nerves. This type of pain often begins immediately after an accident or injury. Traditional treatments with prescription or over-the-counter medications, such as acetaminophen (paracetamol), or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (such as Motrin or Advil) or naproxen (such as Aleve or Naprosyn), and anesthetics, are the mainstay of treatment today. However, these treatments are usually associated with significant side effects (gastrointestinal, cardiovascular, addictive, etc.).

[0003] Over-the-counter NSAIDs primarily target the enzymes that produce prostaglandins called cyclooxygenase. There are two cyclooxygenase enzymes: COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever, but only COX-1 produces prostaglandins that activate platelets and protect the lining of the stomach and intestine. One drawback of NSAID use is that they can reduce secretion of the protective mucus layer in the stomach, causing clinically evident adverse gastrointestinal effects, such as peptic ulcers and the associated risk of bleeding and perforation. On the other hand, curcumin, a compound abundant in turmeric rhizome, is known to inhibit the mRNA and protein expression of COX-2, but not COX-1 (Goel A, Boland CR, Chauhan DP. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett 2001;172:111-118). In addition, curcumin has been shown to suppress the expression of 5-LOX, possibly via downregulation of NF-κB activation. Furthermore, curcumin has been shown to bind to the active site of 5-LOX and inhibit its activity.

[0004] Lipoxygenases (LOX) belong to a multigene genus of dioxygenases that contain a non-heme iron in the active site of the enzyme. Lipoxygenases are classified as 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX is expressed by cells primarily involved in regulating inflammatory, allergic, and other immune responses, such as neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, dendritic cells, and B lymphocytes. In vitro studies performed on rat lung cytosolic fractions showed that curcumin is a competitive inhibitor of 12 / 15 LOX (Bezakova L, Kostalova D, Oblozinsky M, Hoffman P, Pekarova M, Kollarova R, Holkova I, Mosovska S, Sturdik E. Inhibition of 12 / 15 lipoxygenase by curcumin and turmeric extracts. Ceska Slov Farm. 2014 Feb;63(1):26-31. PMID:24568335).

[0005] Another plant-derived compound that inhibits 5-LOX is acetyl-11-keto-β-boswellic acid (AKBA), a derivative of boswellic acid. AKBA is said to inhibit 5-LOX through binding to a pentacyclic triterpene-selective effector site by an enzyme-directed, noncompetitive mechanism (Sailer ER, Subramanian LR, Rall B, Hoernlein RF, Ammon HP, Safayhi H. Acetyl-11-keto-β-boswellic acid (AKBA): structural requirements for binding and 5-lipoxygenase inhibition. Br J Pharmacol. 1996 Feb;117(4):615-8. doi:10.1111 / j.1476- 5381.1996.tb 15235.x. PMID:8646405; PMCID:PMC1909340.). AKBA inhibits 5-LOX well, but no effect on 12 / 15-LOX has been reported. AKBA may also suppress the activity of COX enzymes by direct interaction. AKBA reversibly inhibited COX-1, and COX-2 was inhibited less efficiently by AKBA compared to COX-1 (Siemoneit U, Hofmann B, Kather N, Lamkemeyer T, Madlung J, Franke L, Schneider G, Jauch J, Poeckel D, Werz O. Identification and functional analysis of cyclooxygenase-1 as a molecular target of boswellic acids. Biochem Pharmacol. 2008 Jan 15;75(2):503-13. doi:10.1016 / j.bcp.2007.09.010. Epub 2007 Sep 14. PMID:17945191.).

[0006] Despite ample in vitro evidence that plant-derived compounds have analgesic properties, analgesic plants have rarely been considered for the treatment of musculoskeletal pain because of the slow onset of analgesic effects. Herbal preparations for pain and inflammation are available, but they take a long time to provide relief and are not as effective as synthetic drugs such as ibuprofen, acetaminophen, and acetylsalicylic acid.

[0007] US Patent No. 8,147,882 discloses an herbal formulation containing 12 herbal extracts. The formulation has been studied for its efficacy in a non-randomized open-label study. The turmeric and boswellia extracts used in this patent have low bioavailability, and there is nothing in this formulation to address the lack of bioavailability of the compounds. Therefore, this formulation does not provide immediate pain relief. Furthermore, although there are about 12 herbs used, their benefits are not specified, and the use of multiple herbs increases the risk of allergic reactions. The study did not use a negative or positive control group, and subjects were to rate efficacy based on their memory of using other analgesics. The study parameters used in US Patent No. 8,147,882 may lead to many biases and uncertainties, and therefore the results of this study cannot be taken as conclusive evidence. The study disclosed in Example 3 does not show whether the formulation has a rapid onset of analgesic effect in people experiencing musculoskeletal pain.

[0008] US Patent 9352008 discloses an herbal formulation containing six herbs used to treat pain and stiffness. Human studies conducted with this formulation showed that pain and stiffness disappeared within 2-4 weeks, however, the study does not show whether the formulation has an immediate analgesic effect for those experiencing musculoskeletal pain. The study sample was too small to call the results conclusive. The turmeric extract used in this formulation has low bioavailability, and there is nothing in this formulation that addresses the bioavailability of the compound.

[0009] US Patent Application Serial No. 13 / 030,267 discloses a formulation made from 19 compounds, many of which are plant extracts. The study conducted to demonstrate efficacy in Example 3 is in line with marketing research without substantial data or scientifically relevant questions. The study does not demonstrate whether the formulation provides immediate analgesic benefits to individuals experiencing musculoskeletal pain. Nothing in the formulation addresses the lack of bioavailability of the compounds.

[0010] US Patent Application No. 13 / 911,265 discloses a herbal formulation for topical application. The formulation contains about six extracts and alpha-lipoic acid. Turmeric extract and Boswellia extract are used below their effective doses. Furthermore, turmeric extract rich in curcumin is not recommended for topical use because it stains the skin. Regarding pain relief, a human study is disclosed in Example 2, which showed improvement in musculoskeletal pain after only two weeks. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 8,147,882 [Patent Document 2] US Patent No. 9352008 [Patent Document 3] U.S. Patent Application Publication No. 13 / 030,267 [Patent Document 4] U.S. Patent Application Publication No. 13 / 911,265 Summary of the Invention [Problem to be solved by the invention]

[0012] All of the above references use turmeric or boswellia extracts in their formulas for the treatment of some type of pain, but in both cases the pain relief only occurs after a few days or weeks. There have been no reports of significant immediate pain relief, which may be due to a lack of oral bioavailability of the compounds or a lack of active compounds in the formula. The use of multiple herbs may dilute the effects of the associated active compounds. No synergistic effects are observed in the above formulas, only additive properties.

[0013] Notwithstanding the above, there is a need for plant-based pain relief formulations that provide pain relief that is equal to or better than NSAIDs. Most NSAIDs have some side effects, but plant-based products fall into the low-risk profile. It is generally believed that plant-based pain relief formulations are not a substitute for pharmaceutical pain relief products. This application discloses formulations and methods that change that view. Objectives of the Invention

[0014] The main objective of the present invention is to provide an oral pain relieving formulation made from plant extracts which provides faster pain relieving effects.

[0015] Another object is a method for the rapid treatment of musculoskeletal pain using a plant-derived preparation.

[0016] Yet another object is to develop a method for producing pharmacologically effective pain relieving formulations using plant parts. [Means for solving the problem]

[0017] This document discloses a musculoskeletal pain reliever made from plant-derived formulations, particularly solid turmeric extract and solid boswellia extract, which provides faster pain and inflammation relief to those in need. Also disclosed is a method for making the formulation. Also disclosed herein is a method for managing pain in subjects experiencing acute musculoskeletal pain to speed up the pain relief process.

[0018] The present invention relates to a plant-based formulation for fast-acting pain relief and a method for preparing said pain relief formulation. More specifically, the present invention relates to a plant-based musculoskeletal pain relief formulation comprising a solid turmeric extract and a solid boswellia extract in oil in a weight ratio of about 2.8:1 to 3:1, and having a hydrophilic-lipophilic balance value of 10 to 19. The pain relief agent contains curcuminoids and acetyl-11-keto-beta-boswellic acid in a ratio of 2:1 to 99:1. The administration of said analgesic and anti-inflammatory formulation speeds up the analgesic process in subjects experiencing acute musculoskeletal pain.

[0019] The painkiller formulation disclosed herein is a mixture of a solid turmeric extract containing curcuminoids and a solid boswellia extract containing acetyl-11-keto-beta-boswellic acid. The mixture is oil loaded with a hydrophilic lipophilic balance value ranging from 10 to 19. In the painkiller formulation, the curcuminoids and acetyl-11-keto-beta-boswellic acid are in a ratio of 2:1 to 99:1. The curcuminoids consist of curcumin, bisdemethoxycurcumin, and demethoxycurcumin, which are obtained from the rhizome of turmeric, and acetyl-11-keto-beta-boswellic acid is obtained from boswellia resin.

[0020] In an embodiment, the pain relieving formulation is a mixture of solid turmeric rhizome and boswellia extracts uniformly dispersed in oil, the mixture to oil weight ratio is 1:10 to 1:1. Further, the mixture of solid turmeric extracts has a solid boswellia extract containing at least 90% curcuminoids and at least 10% acetyl-11-keto-beta-boswellic acid. The turmeric extract and boswellia extract are in a weight ratio of 1:1 to 10:1, and the mixture is loaded in oil with an HLB value ranging from 10 to 19. Further, the average particle size of the turmeric and boswellia extracts is greater than 100 nanometers and less than 200 micrometers.

[0021] In yet another embodiment, a method for accelerating the onset of analgesia in a subject experiencing acute musculoskeletal pain is disclosed. An effective amount of a combination of solid turmeric extract and solid boswellia extract formulated in oil having a hydrophilic-lipophilic balance value of 10 or more and 19 or less is required for administration to a subject in need. More precisely, the onset time of analgesia is 30-210 minutes when administered at about 10-25 mg per kg body weight in a formulation containing curcuminoids and acetyl-11-keto-beta-boswellic acid in a weight ratio of 30:1 to 10:1.

[0022] In yet another embodiment, a method for preparing an analgesic formulation is disclosed. The method for preparing a plant-derived formulation that provides rapid analgesia by enhancing oral bioavailability includes the steps of: a) mixing a solid turmeric extract with a solid boswellia extract in a weight ratio of about 2.8:1 to 3:1; b) adding the mixture to edible oil and mixing well to obtain a high viscosity mixture; c) passing the resulting mixture through a bead mill several times to obtain a yellow liquid with a viscosity in the range of 270 to 320 mP·s.

[0023] The mixture of solid turmeric extract and solid boswellia extract is blended with at least 50% oil. The mixture is then milled until it is uniformly dispersed in the oil. The composition is further milled until the particle size of the mixture is less than 200 micrometers and greater than 100 nanometers. An antioxidant comprised of a combination of rosemary and green tea extracts is administered at 2000 ppm of the edible oil as a preservative. Other features of the disclosure will become apparent from the detailed description that follows. Detailed Description of the Invention

[0024] The present invention specifically discloses a plant-derived formulation made from a mixture of solid turmeric extract and solid boswellia extract loaded in oil, with a hydrophilic-lipophilic balance value ranging from 10 to 19 and rapid pain relief effects, as well as a method for producing said pain-relieving formulation. The C urcuminoids present in the solid turmeric extract and the acetyl-11-keto-beta-boswellic acid present in the solid boswellia extract are in a ratio of 2:1 to 99:1. Administering said analgesic plant-derived formulation to a subject experiencing acute musculoskeletal pain expedites the process of pain relief. Each novel feature is disclosed through several embodiments. Through these embodiments, compositions, formulations, and products are disclosed along with processes of manufacture and methods of use. The embodiments should be understood in their broadest sense. The figures also reveal the effectiveness of said formulation against known equivalents through various in vivo and in vitro studies. The figures of the present invention are intended to enable those skilled in the art to better understand the invention and are not intended to narrow the scope of the claimed subject matter.

[0025] The present invention relates to formulations and methods for the treatment and management of pain in subjects in need thereof. Unlike other herbal extracts that offer little efficacy, the formulations disclosed herein are effective in providing significant and more rapid pain relief.

[0026] Curcuminoids as referred to in this application refer to compositions, solutions, or extracts containing at least 50% by weight of curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids include solvent extracts of turmeric rhizome, oleoresins from turmeric rhizome, synthetic curcumin and its analogs, curcumin-enriched turmeric powder, or combinations thereof.

[0027] Acetyl-11-keto-boswellic acid (AKBA) is also called acetyl-keto-β-boswellic acid or acetyl-keto-boswellic acid. AKBA can be an isolated pure form of AKBA, or a synthetic form of concentrated extract of Boswellia obtained from Boswellia (Serrata) resin, or a combination thereof.

[0028] "Pain" as used herein refers to acute and chronic musculoskeletal pain, including pain caused by physical trauma, inflammation, back pain, toothache, headache, menstrual cramps, sore throat, fever, and rheumatic pain, such as pain associated with joint pain, arthritis, ankylosing spondylitis, and systemic connective tissue disorders, and pain caused by cancer.

[0029] An embodiment of an analgesic formulation is disclosed, the formulation being a mixture of curcuminoid and AKBA, the mixture is loaded in oil, and the hydrophilic lipophilic balance value is 10-19. The combination of curcuminoid and AKBA in the analgesic formulation is 2:1-99:1 w / w. The most preferred combination of curcuminoid and AKBA for analgesic effect is 10:1-30:1 w / w. "Loaded" or "loaded" refers to the homogeneous mixing of a solid compound in an immiscible liquid, which can be achieved by applying physical force to the mixture to form a homogeneous dispersion. The oil used is an edible oil selected from the group consisting of, but not limited to, sesame oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew nut oil, canola oil, corn oil, safflower oil, cottonseed oil, ramucil oil, niger oil, hemp oil, turmeric oil, ginger oil, animal fat, fish oil, medium chain triglycerides, saturated fatty acids, unsaturated fatty acids, or combinations thereof. The mixture to the oil is in a w / w ratio of 1:99 to 3:2, and the mixture is uniformly dispersed in the oil. More preferred mixing ratios of the mixture to the oil are 1:10 to 1:1, 1:5 to 1:1, and 40% to 60% of the mixture by weight to be blended in the oil. The mixture referred to here is a combination of solid curcuminoids and AKBA.

[0030] In a preferred embodiment, the formulation is a mixture of solid turmeric extract and solid boswellia extract, the mixture being filled into an oil base. The turmeric extract is enriched with at least 80% curcuminoids and up to 98% curcuminoids w / w. The curcuminoids consist of curcumin, bisdemethoxycurcumin, and demethoxycurcumin. The solid boswellia extract is enriched with boswellic acids, with at least 10% of the extract being AKBA. The preferred oil for the formulation is a vegetable oil, which may be selected from the group consisting of, but is not limited to, sesame oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew nut oil, canola oil, corn oil, safflower oil, cottonseed oil, ramucil oil, niger oil, hemp oil, turmeric oil, ginger oil, medium chain triglycerides of vegetable origin, or combinations thereof. The mixture to oil is in a weight ratio of 1:99 to 3:2, and the mixture is uniformly dispersed in the oil. More preferred blends of the mixture to the oil are 1:10 to 1:1, 1:5 to 1:1, and 40% to 60% of the mixture by weight is loaded into the oil.

[0031] In a preferred embodiment, the formulation is a mixture of solid turmeric extract and solid boswellia extract, and the mixture is filled into an oil base. The turmeric extract contains at least 80% curcuminoids and up to 98% w / w curcuminoids. The curcuminoids consist of curcumin, bisdemethoxycurcumin, and demethoxycurcumin. The solid boswellia extract contains boswellic acids, and at least 10% of the extract is AKBA. The weight ratio of the turmeric extract to the boswellia extract is about 1:1 to 3:1, more preferably 2.8:1 to 3:1. The preferred oil for the formulation is omega-3 rich fish oil, or a combination of omega-3 rich vegetable oil and fish oil. The weight ratio of the mixture to the oil is 1:99 to 1:1, and the mixture is uniformly dispersed in the oil. The weight ratio of the mixture to the oil is 1:99 to 3:2, and the mixture is uniformly dispersed in the oil. More preferred blends of the mixture with oil are 1:10 to 1:1, 1:5 to 1:1, and where the mixture is loaded into the oil at 40% to 60% by weight.

[0032] In a preferred embodiment, the formulation is a mixture of solid turmeric extract and solid boswellia extract, which is blended with oil. The turmeric extract is rich in curcuminoids, with at least 80% curcuminoids and up to 98% curcuminoids w / w. The curcuminoids consist of curcumin, bisdemethoxycurcumin, and demethoxycurcumin. The solid boswellia extract is rich in boswellic acids, with at least 10% of the extract being AKBA w / w. More preferably, the formulation is made with 10-50% turmeric extract, 1-30% boswellia extract, and 40-90% sesame oil. More preferably, the formulation is made with about 30±2% turmeric extract, about 10±2% boswellia extract, and about 60±2% sesame oil.

[0033] In a preferred embodiment, the formulation also contains a natural preservative selected from the group consisting of cinnamon bark oil, citric acid, rosemary extract, clove bud oil, celery seed oil, oregano, cardamom, vanilla, nutmeg fruit extract, cumin seed, ascorbic acid, cinnamon leaf, and cinnamon extract. The natural preservative may represent 0.1-10% of the weight of the formulation, more precisely, the preservative in the formulation may be 100-5000 ppm.

[0034] In yet another embodiment, the curcuminoids and AKBA, or solid turmeric extract and solid boswellia extract formulated in the oil, have a particle size of about 100 nanometers to 200 microns. Over 90% of the particles dispersed in the oil have a fraction size ranging from 900 nanometers to 5 microns.

[0035] One embodiment of a method for the preparation of an analgesic formulation is disclosed. A mixture is prepared by mixing solid turmeric extract (about 95% curcuminoids) with solid boswellia extract (about 10% AKBA and at least 30% boswellic acid) in a ratio of 2.8:1. The mixture is added to edible oil (sesame oil in this example) in a ratio of 2.8:1:6.2 and mixed well to obtain a highly viscous mixture. The mixture thus made is passed through a bead mill. Antioxidants are dosed at 2000 ppm of preservatives, which are a combination of rosemary and green tea extracts. The mixture is then passed through a bead mill five times to obtain a yellow liquid with a viscosity in the range of 270-320 mP·s.

[0036] Activity of the formulation Another aspect of the invention is a method for hastening the onset of analgesic effects in a subject experiencing acute musculoskeletal pain. The subject is administered an effective amount of a mixture of solid turmeric extract and solid boswellia extract, the mixture being loaded into an oil having a hydrophilic lipophilic balance value ranging from 10 to 19. The solid turmeric extract and solid boswellia extract are in a weight ratio of 1:1 to 3:1 in the formulation, with a preferred combination of solid turmeric extract and solid boswellia extract for analgesic effects being 2.8:1 to 3:1. "Loaded" or "loaded" refers to the homogeneous mixing of solid compounds into an immiscible liquid, which can be achieved by applying physical forces to the mixture to form a homogeneous dispersion. The subject can be a human or an animal, and in the case of a human, an analgesic effect is onset within 30 to 210 minutes upon administration of an effective amount of a mixture of solid turmeric extract and solid boswellia extract, the mixture being loaded into an oil. The oil used is an edible oil selected from the group consisting of sesame oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew oil, canola oil, corn oil, safflower oil, cottonseed oil, ramucil oil, niger oil, hemp oil, turmeric oil, ginger oil, animal fat, fish oil, medium chain triglycerides, saturated fatty acids, unsaturated fatty acids, or combinations thereof. The weight ratio of the mixture to the oil is 1:99 to 3:2, and the mixture is uniformly dispersed in the oil. More preferred blends of the mixture and the oil are 1:10 to 1:1, 1:5 to 1:1, and 40% to 60% of the mixture by weight is loaded into the oil.

[0037] In one embodiment, a method for hastening the onset of analgesia in a subject experiencing acute musculoskeletal pain comprises administering a blend of solid turmeric extract and solid boswellia extract in an amount of 200 mg to 800 mg. The blend is a mixture of solid turmeric extract and solid boswellia extract in a weight ratio of 1:1 to 3:1, and the blend is packed into edible oil. Ideally, the average portion size of the loaded blend in the oil ranges from 100 nanometers to 200 microns.

[0038] In one embodiment, the subject is a human or animal, and in humans, the onset of the analgesic effect is achieved within 30 to 210 minutes after oral administration of the formulation.

[0039] In one embodiment, all of the formulations disclosed above are in oral dosage form, and the dosage form is selected from the group of soft gel capsules, hard shell capsules, tablets, mini tablets, granules, sachets, powders, pastes, injections, ampoules, solutions, suspensions, emulsions, pills or creams. The dosage form is packaged in dosage units of 500-1000 mg, each unit containing about 200 mg-800 mg of the mixture with the remainder being edible oil.

[0040] The treatment group showed a 97.85% improvement compared to 2.46% in the placebo group in the cumulative responder analysis (AUC method) and a significant reduction in pain intensity (SPID6rest p<0.001). The onset of pain relief was faster in the treatment group, with 99% of subjects showing a mean PPR at 68.5 minutes and 96% of subjects showing a mean MPR at 191.6 minutes compared to the placebo group, which was highly significant. A highly significant and sustained improvement in pain relief was observed in the treatment group, with 93% of subjects showing 50% or more of maximum TOTPAR6 and a number needed to treat at rest of 1.1. The treatment group showed clinically significant improvements in standardized response means for the SF-MPQ score of 2.31 total, 1.77 sensory, 1.15 affective, 5.51 visual analogy score, and 4.88 current pain index compared to placebo.

[0041] Musculoskeletal pain may be induced by exercise and may be selected from the group consisting of low back pain, generalized pain, muscle pain, headache, neck pain, limb pain, grade 1 sprain, joint pain, acute soft tissue injury, acute ligament injury, and acute tendon injury. The rapid and sustained pain relief may be the result of blocking multiple pain pathways at once. A synergistic effect was observed between curcuminoids and boswellic acid compared to their respective actions.

[0042] In one embodiment, a method for accelerating the onset of analgesia in subjects experiencing acute musculoskeletal pain in different body regions comprises administering a combination of turmeric and boswellia at a dose of 1000 mg. In all five pain regions and three modalities of rest, movement and pressure, head and neck, upper and lower extremities, and trunk, the treatment group showed a significant reduction in pain intensity compared to placebo. The treatment group showed 100% relief of head and neck pain intensity using the numerical rating scale pain after 6 hours. Pain relief began as early as 40 minutes, with complete pain relief achieved as early as 160 minutes. In the upper extremities and trunk categories, the treatment group showed 99% and 97% relief of pain intensity after 6 hours. The upper extremities and trunk categories showed close PPR at 52 and 76 minutes, with MPRs of 168 and 216 minutes, respectively. In the general pain category, treatment groups achieved pain relief at 75 minutes and complete pain relief at 240 minutes. In the lower limb category, PPR achieved pain relief at 74 minutes and MPR achieved pain relief at 176 minutes, with a 97% reduction in pain intensity after 6 hours.

[0043] In another preferred embodiment, rapid analgesia in subjects with acute musculoskeletal pain is achieved by administering an analgesic formulation. There is a significant difference in LSM PID of treatment from 270 minutes after administration. The sum of pain intensity difference (SPID6) and area under the pain intensity effect curve (AUE6) showed a significant difference at 360 minutes when compared with placebo. In the cumulative responder analysis, 61.93% improvement was observed in the treatment group, whereas 2.7% improvement was observed in the placebo. The mean TOTPAR at 6 hours is 198 in the treatment group and 32 in the placebo group. There is a statistically significant difference in analgesia between the treatment group and the placebo group at 360 minutes.

[0044] The mean remaining time to restriction (RMST) in the treatment group is 269 minutes compared to 312 minutes in the placebo group, and pain relief is significantly better than in the placebo group. The quality of pain assessed by the McGill questionnaire is analyzed using Wilcoxon and paired t-tests. There are significant differences in the sensory, emotional domain, and total score of the MPQ in the treatment group, but no significant change in the placebo group. There are also significant differences in the VAS and PPI in the treatment group, but no significant change in the placebo group.

[0045] In one embodiment, the efficacy of the fast-acting analgesic formulation for menstrual pain associated with primary dysmenorrhea is disclosed. The sum of pain intensity differences (SPID6) showed significant differences at 360 minutes when compared to the placebo group. The mean TOTPAR at 6 hours is 19 for the treatment group and 2 for the placebo group. At 360 minutes, there is a statistically significant difference in analgesia between the treatment and placebo groups. In the treatment group, 73.3% reported excellent analgesia and 26.7% reported very good analgesia. Meanwhile, in the placebo group, 83.3% reported poor analgesia.

[0046] In another embodiment, the efficacy of sesame oil blend of turmeric and boswellia extracts against exercise-induced acute musculoskeletal pain was compared with turmeric and boswellia extract powder. The dose was a single dose of 2*500mg capsules. The sum of pain intensity differences at 6 hours showed that the treatment group had significantly lower pain intensity at rest, compression and movement (SPID6rest, SPID6pres, SPID6mov) compared with the extract powder and placebo. The mean total pain relief at 6 hours in the treatment group was significantly better than the extract powder group. At rest, compression and movement, 98% of subjects in the treatment group reported pain relief of more than 50% of maximum TOTPAR, compared with only 6% in the placebo group. In the extract powder group, only 2% reported pain relief of more than 50% of maximum TOTPAR during movement, compared with 6% at rest and compression. EXAMPLES

[0047] Specific embodiments of the present invention will be described with reference to the following general preparation methods and examples. It should be understood that these examples are disclosed only to illustrate the present invention and are not intended to limit the scope of the present invention. These examples are not intended to limit the foregoing description. Example 1

[0048] The process for producing a formulation containing turmeric and boswellia extract in a 3:1 ratio

[0049] The mixture was prepared by mixing 28 kg of solid turmeric extract (about 95% curcuminoids) with 10 kg of solid boswellia extract (about 10% AKBA and at least 30% boswellic acid). The mixture was added to 62 kg of edible oil (sesame oil in this example) and mixed well to obtain a highly viscous mixture. The mixture thus prepared was passed through a bead mill, where the strong reciprocal movement of the grinding media created large shear, compression, and abrasive forces to grind the material. The preservative antioxidant was dosed at 2000 ppm of the oil, so the preservative was a combination of rosemary and green tea extracts. The mixture was passed through the bead mill five times to obtain a yellow liquid with a viscosity in the range of 270–320 mP·s (this will be called sample 1). Example 2

[0050] Process for producing a formulation with a 10:1 ratio of curcuminoids to boswellic acids

[0051] The mixture was prepared by mixing 10 kg of solid curcuminoids (purity about 98%) with 1 kg of solid boswellic acid (AKBA about 34%). The said mixture was added to 17 kg of edible oil (sesame oil in this example) and mixed well to obtain a highly viscous mixture. The mixture thus prepared was passed through a bead mill. In the bead mill, the strong reciprocal movement of the grinding media formed large shear, compression, and abrasive forces to grind the materials. Antioxidants as preservatives were added at 2000 ppm to the oil, and the preservative was a combination of rosemary and green tea extracts. The mixture was passed through the bead mill five times to obtain the final formulation (sample 1). The formulation was a yellow liquid with a viscosity in the range of 270-320 mP·s. Example 3

[0052] Sample 1 of Example 1 was filled into softgel capsules to form a dosage form. Each softgel capsule contained 500 mg of Sample 1. Each capsule contained approximately 133 mg of curcuminoids and approximately 5 mg of AKBA. TIFF2025508390000001.tif63159 Example 4

[0053] Rapid pain relief by administration of analgesics in cases of exercise-induced acute musculoskeletal pain (MSP)

[0054] This multicenter study analyzed the efficacy of a formulation of turmeric and boswellia extract in sesame oil produced according to Example 1. In this study, 232 subjects were randomly assigned to receive a single dose of 1000 mg of Sample 1 (treatment) or placebo in a 1:1 allocation ratio. The study included healthy male and female subjects aged 18-65 years with exercise-induced acute MSP with a resting NRS of 5 or greater on a scale of 0-10 that occurred within 24 hours of arriving at the facility. Subjects who met all inclusion and exclusion criteria were randomly assigned to receive either the study intervention Sample 1, 1000 mg (500 mg x 2 softgels) containing 266 mg of curcuminoids and 10 mg of acetyl keto boswellic acid or the comparison intervention, 1000 mg of the corresponding placebo. Investigators and subjects were blinded using placebos similar in size, color, packaging, and labeling. All staff involved in the study were blinded to what the treatment was.

[0055] The primary outcome was the change in total pain intensity difference at rest (SPID6rest) at 6 hours calculated from the numerical rating scale (NRS). Secondary outcomes were time to perceptible pain relief (PPR) and time to significant pain relief (MPR) using the double stopwatch method (from onset of analgesia to analgesia), SPID6 with motion (SPID6move) and pressure (SPID6pres), total pain relief at 6 hours at rest (TOTPAR6rest), with motion (TOTPAR6move) and with pressure (TOTPAR6pres) using the pain relief scale (PRS), and change in quality of pain using the shortened version of the McGill Short Form Questionnaire (SF-MPQ). Outcomes were assessed without unblinding to the intervention. Outcomes derived from the NRS score were pain intensity difference (PID), SPID at 180 and 360 minutes. Areas under the PID curves at 180 and 360 minutes and cumulative responder analysis proportions (CPRA) from the AUC curves at rest, exercise, and compression. Numbers needed to treat (NNT) were calculated as additive outcomes of PRSrest,move,pres.

[0056] Numeric Pain Rating Scale (NRS)

[0057] The NRS is an 11-point scale, with 0 being "no pain" and 10 representing the worst pain imaginable. A rating score of 1 to 4 is considered mild, 5 to 6 moderate, and 7 to 10 severe. The NRS was measured at 30-minute intervals for up to 6 hours at rest (NRSrest), during movement of the affected area (NRSmove), and during pressure on the affected area to calculate SPID6rest,move,pres.

[0058] Pain Relief Scale (PRS)

[0059] The pain relief scale is a categorical scale showing a positive progression from "no relief," "a little relief," "some relief," "much relief" to "complete relief" (coded from 0 to 4). TOTPAR is the area under the time-analgesic effect curve at a specific time. PRS was measured at 30-minute intervals up to 6 hours to calculate TOTPAR6. PRS was measured while the subject was at rest (PRSrest), during movement of the affected area (PRSmove), and during pressure on the affected area (PRSpres).

[0060] Until analgesic effect appears

[0061] The onset of analgesia was measured using the "double stopwatch" method. After administration, two stopwatches were started simultaneously. The first stopwatch was stopped when the subject reported first perceptible pain relief (PPR). The second stopwatch was stopped when the subject felt complete pain relief, called significant pain relief (MPR). Times to PPR and MPR were recorded in hours and minutes and were censored if PPR / MPR was not reached within 6 hours.

[0062] Short version of the McGill Pain Questionnaire (SF-MPQ)

[0063] The McGill Pain Questionnaire (MPQ), which allows subjects to describe the quality (affective domain) and intensity (sensory domain) of their pain, was completed at the beginning and end of the study. Participants also rated their current pain intensity (PPI) on a scale of 0 to 5. Pain intensity was assessed on a horizontal VAS ranging from 0 to 100 mm, with no pain (score 0) and worst pain (score 100) as reference points.

[0064] In this study, 235 subjects were screened, 38 subjects each at four sites and 40 subjects each at two sites, resulting in the enrollment of 232 subjects. There were no significant differences between the groups in baseline parameters of NRSrest (p=0.053), NRSmove (p=0.357), and NRSpres (p=0.266). There were also no significant differences in demographic variables of age (p=0.919), height (p=0.747), and weight (p=0.846). Demographic and baseline data for the treatment and placebo groups are shown in Table 1. Enrolled subjects had exercise-induced pain in the lower back (n=70), shoulder (n=22), knee (n=20), lower body (n=22), musculoskeletal (n=6), and other types of pain (n=92). There were no adverse events and no dropouts in this study.

[0065] NRS at rest, exercise and compression

[0066] The summed pain intensity difference (SPID) and area under the curve (AUC) for NRSrest,move,pres at 180 and 360 minutes showed significant differences (p<0.001) between treatment and placebo groups and are shown in Table 1. AUC responder analysis using NRSrest,move,pres recorded differences of 95.39%, 93.52%, and 93.28%, respectively, compared to placebo responders at the end of 6 hours. TIFF2025508390000002.tif104159

[0067] Least squares mean (LSM) differences between treatment and placebo showed statistically significant differences in all categories (NRSrest, move, pres) at specific time points from 1 hour to the end of the study. NRS analyses showed that treatment reduced acute pain intensity, which was both statistically and clinically significant. Details of the responder analyses and LSM PIDs of treatment and placebo for NRSrest, move, pres are shown in Tables 2a, 2b, and 2c. TIFF2025508390000003.tif112159TIFF2025508390000004.tif127166TIFF2025508390000005.tif107159

[0068] Until analgesic effect appears

[0069] The onset of pain relief was faster and highly significant in the treatment group, with 99.1% of subjects experiencing PPR and 95.7% achieving MPR, compared with 10.4% of subjects in the placebo group experiencing PPR and 1.7% achieving MPR. Because pain relief was relatively low in the placebo group, it was not possible to estimate the median pain relief time from the observational data. Restricted mean remaining time (RMST) analysis showed PPR of 68.5 minutes and MPR of 191.6 minutes in the treatment group and 340.7 minutes and 358.1 minutes in the placebo group, respectively. The RMST ratio indicates that those in the treatment group experienced PPR 4.98 times faster and achieved MPR 1.87 times faster than those on placebo. The RMLT ratios of 0.07 (PPR) and 0.01 (MPR) indicate that the placebo group experienced a 93% and 99% reduction in pain-free time, respectively. A lower RMST or higher RMLT in MPR and PPR indicates shorter pain duration in the treatment group and an overall benefit compared with the placebo group.

[0070] Kaplan-Meier (KM) residual plots of PPR showed that 45 (39%) subjects in the treatment group experienced PPR within 30 minutes and 115 (99%) experienced PPR after 190 minutes, whereas 2 (1.7%) subjects in the placebo group experienced PPR within 30 minutes and 12 (10.3%) experienced PPR after 285 minutes. The earliest MPR was achieved within 75 minutes (1 patient), and 111 (96%) subjects experienced MPR within 360 minutes, whereas only 2 events (1.7%) occurred at 360 minutes in the placebo group.

[0071] Pain Relief Scale (PRS)

[0072] TOTPAR6 rest, move, and the pres showed significant differences between the two groups, demonstrating the superior efficacy of the treatment to obtain pain relief. The treatment effect in terms of the number of patients needed to be treated to obtain 50% of maximum pain relief (NNT) in the treatment group was 1.1 at rest, during movement, and during compression. The number of subjects with 50% or more of maximum TOTPAR was 108, 109, and 109 in the treatment group (p<0.001 for PRSrest, move, and pres) and 3, 1, and 1 in the placebo group (Table 3). TIFF2025508390000006.tif92166

[0073] RMST to achieve maximum pain relief by KM analysis at rest, motion, and compression were 194, 197.7, and 194.2 minutes in the treatment group compared with 345.5, 345.5, and 356.7 minutes in the placebo group, respectively, which was statistically significant. Higher RMST (restricted mean remaining time to maximum pain relief) or lower RMTL (restricted mean lost time to maximum pain relief) to achieve maximum pain relief at PRS rest, motion, and compression. The treatment group showed faster pain relief, indicating an overall advantage compared to the placebo group (Table 4). In the treatment group, 50% of subjects experienced maximum pain relief at 180, 182, and 180 minutes (median) for rest, motion, and compression, respectively. The median could not be assessed in the placebo group. TIFF2025508390000007.tif132159

[0074] Repeated measures proportional odds logistic regression analysis showed that pain relief increased with time, represented by the negative time coefficient, which was significant in both the treatment and placebo groups. Although this analysis showed a significant effect in the placebo group, the odds of experiencing complete pain relief in the same period were negligible compared to the treatment. The cumulative probability odds of obtaining complete pain relief in the placebo group compared to the treatment group were 0.00025, 0.00025, and 0.00024 times for rest, movement, and compression, respectively (Table 5). TIFF2025508390000008.tif87166

[0075] Short version of the McGill Pain Questionnaire (SF-MPQ)

[0076] The treatment group showed statistically significant reductions in the McGill Pain Questionnaire (MPQ), visual analog scale (VAS), total, sensory and emotional domains of the Present Pain Index (PPI) when comparing pre- and post-treatment, whereas the placebo group showed no significant change in MPQ (p>0.05), but significant changes were observed in VAS and PPI. SRM values ​​above 0.80 indicated clinically significant improvement, with the treatment group showing values ​​above 0.8 in MPQ, VAS and PPI, whereas the placebo group showed values ​​below 0.5 in MPQ, VAS and PPI, indicating no beneficial change. A change of 13.7 mm in VAS indicated the minimal clinically important difference (MCID), with the treatment group showing a reduction that exceeded the MCID (mean difference 78.6 mm), whereas the change in the placebo group was below the MCID (Table 6). TIFF2025508390000009.tif135166

[0077] Most of the scales used to evaluate acute pain management are unidimensional, such as the NRS or VAS, measuring the intensity of pain. Because pain is multidimensional, using only one in a study does not provide the complete picture. The combined use of the NRS and PRS for pain assessment improved the objectivity of pain assessment compared with using the VAS or NRS alone. The objectivity of the assessment was further improved by measuring the time to onset of analgesia using the double stopwatch method. To confirm the multidimensional nature of pain, a shortened version of the McGill Pain Questionnaire was used. Changes in NRS pain scores and their effect on pain relief in patients with moderate pain showed that a decrease of 1.3, 2.4, and 3.5 units in the NRS corresponded to a minimal improvement, a large improvement, and a very large improvement in the degree of pain relief.

[0078] Most clinical trials using the NRS tend to consider only pain relief at rest or during movement separately, which significantly underestimates the reduction in pain intensity and leads to reporting bias. Therefore, in this study, we measured the reduction in pain intensity not only at rest, but also for movement and applied pressure on the affected area to determine the overall effectiveness of the treatment. It can be seen that the majority of subjects had higher NRS scores for movement and pressure than at rest at baseline. The primary efficacy variable NRS at rest showed a significant reduction in pain intensity (SPID180 and 360) in 95% of responders compared with placebo. The fact that there was almost similar pain relief with movement indicates that the treatment is effective in improving the function of the affected area. The improvement in pain intensity reduction when pressure is applied to the affected area indicates that the treatment is effective in relieving pain due to acute inflammation. Example 5

[0079] Pain relievers are administered to rapidly relieve acute exercise-induced musculoskeletal pain in various body sites.

[0080] This randomized, placebo-controlled, multicenter study was conducted to analyze whether a blend of turmeric and boswellia extracts in sesame oil, produced according to Example 1, is effective for acute musculoskeletal pain in different parts of the body, namely, head and neck, trunk, upper and lower limbs. In this study, 232 healthy subjects of both sexes, aged 18-65 years, who experienced acute musculoskeletal pain within 24 hours prior to the clinic visit, were randomized in a 1:1 ratio to receive a single dose of 1000 mg of sample 1 (treatment) or placebo. Participants were classified according to the location of pain, namely, head and neck, upper limbs, lower limbs, trunk, and whole body after exercise. Pain intensity was measured using a numerical rating scale (NRS), and subjects with a score of 5 or higher were considered eligible for enrollment. Subjects who met all inclusion and exclusion criteria were randomly assigned to receive either the study intervention sample 1, 1000mg (500mgx2 softgels) containing 266mg of curcuminoids and 10mg of acetyl ketoboswellic acid or the corresponding comparison intervention, 1000mg of placebo. Researchers and subjects were blinded using a placebo of similar size, color, packaging and label. All staff involved in the study were blinded to what the treatment was.

[0081] This study focused on analyzing data categorized based on the location of musculoskeletal pain reported by subjects at the time of study enrollment. Pain location was classified into five categories: head and neck: neck Core: Back, pelvis Upper limbs: shoulders, hands, arms, forearms, clavicles, wrists, elbows Lower limbs: hip and thigh muscles, leg and foot muscles, knees, ankles

[0082] General musculoskeletal pain

[0083] The primary objective of the study was to determine the efficacy of the formulation by measuring pain intensity. Pain intensity was measured by the Numeric Pain Rating Scale (NRS). The NRS is an 11-point scale, with 0 representing "no pain" and 10 representing the worst pain imaginable. Rating scores of 1-4 are considered mild, 5-6 moderate, and 7-10 severe. The NRS was measured every 30 minutes after dosing for up to 6 hours while the subjects were sitting at rest (NRSrest), moving the affected area (NRSmove), and applying pressure to the affected area. The sum of the differences in pain intensity was calculated from baseline over 6 hours (SPID6).

[0084] The onset of analgesia was measured using the "double stopwatch" method. After administration, two stopwatches were started simultaneously. The first stopwatch was stopped when the subject reported first perceptible pain relief (PPR). The second stopwatch was stopped when the subject felt complete pain relief, called significant pain relief (MPR). Median remaining time and limit mean remaining time (RMST) analyses of the onset of analgesia were performed. Limit mean remaining time (symptom resolution time) is a measure of treatment effect and is the average of the duration of pain that subjects felt from time 0 until the pain ceased at time t. The RMST difference measures the treatment effect relative to limit symptom resolution time at t. The RMST value is also an absolute measure of symptom resolution time, and this dual mode of presentation as both an absolute and relative measure is an additional advantage of this measure.

[0085] A total of 232 subjects were enrolled and were classified into five groups based on pain location. The most common locations of musculoskeletal pain were trunk (n=85) and lower limbs (n=76), followed by upper limbs (n=47). Fourteen subjects reported head and neck pain, and 10 subjects reported general musculoskeletal pain. The distribution of pain by location was not statistically different in both treatment and placebo groups. There were no significant differences in the distribution of pain by gender and location in both groups.

[0086] Reductions in pain intensity in the categories of head and neck, lower limbs, trunk, upper limbs, and whole body pain were highly significant in the treatment group in the three modalities of rest, movement, and pressure. In general musculoskeletal pain (n=4), there was a near-significant reduction in all three modalities of NRS measurement.

[0087] Treatment response over 360 minutes (6 hours) was summarized as the sum of pain intensity differences (SPID6). In this study, the treatment response was significantly better than the placebo group at rest, during movement, and during compression. The treatment group showed significant reductions in pain intensity compared with the placebo group in all five categories: general musculoskeletal pain, head and neck pain, lower and upper limbs, and trunk. The placebo group did not show significant reductions in any of the five categories of pain location.

[0088] head and neck TIFF2025508390000010.tif77166

[0089] In the treatment group, head and neck pain intensity was reduced by 100% after 6 hours using the Numeric Rating Scale. TIFF2025508390000011.tif55166TIFF2025508390000012.tif101166

[0090] Subjects in the head and neck category had the fastest PPR at 40 minutes and MPR at 160 minutes.

[0091] upper limb TIFF2025508390000013.tif78166TIFF2025508390000014.tif66166TIFF2025508390000015.tif111166

[0092] In the upper extremity category, PPR was close behind at 52 minutes, while MPR was 168 minutes.

[0093] Core TIFF2025508390000016.tif59166TIFF2025508390000017.tif69166TIFF2025508390000018.tif109166

[0094] In the core category, PPR was close behind with 76 minutes and MPR with 216 minutes.

[0095] lower limbs TIFF2025508390000019.tif69166TIFF2025508390000020.tif59166TIFF2025508390000021.tif99166

[0096] The lower extremity categories were close at 74 minutes for PPR and 176 minutes for MPR.

[0097] The placebo group did not see a significant reduction in any of the five categories of pain location.

[0098] General pain TIFF2025508390000022.tif59166TIFF2025508390000023.tif55166TIFF2025508390000024.tif99166

[0099] The treatment group showed a significant reduction in pain intensity compared to the placebo group in all five pain locations and three modalities: rest, movement and compression, head and neck, upper and lower limbs, and trunk. The test formulation is safe and effective for acute pain, regardless of the location of pain. In conclusion, the treatment group was effective in reducing pain at the head and neck, upper and lower limbs, trunk, and whole body sites. In the five major pain locations, the treatment group showed a reduction in pain intensity of 96% or more in all modalities of rest, movement, and compression, whereas the placebo group showed little change. The study results suggest that the efficacy of the test formulation can be positively considered as a rapid relief of acute pain, regardless of the location of pain. Importantly, the formulation may be a safe alternative to analgesics such as NSAIDs that are commonly recommended for acute pain. Example 6

[0100] Providing painkillers for patients with acute musculoskeletal pain provides rapid pain relief

[0101] This randomized placebo-controlled study was conducted to analyze the efficacy of a formulation of turmeric and boswellia extract in sesame oil for acute musculoskeletal pain. In this study, 40 healthy men and women aged 18-65 years who developed acute musculoskeletal pain within 24 hours prior to clinic visit were randomized in a 1:1 ratio to receive a single dose of the test formulation or placebo. The primary outcome measures were the sum of pain intensity differences at 6 hours (SPID6) assessed using the numerical rating scale (NRS) and total pain relief (TOTPAR6) assessed using the categorical pain relief scale (PRS) every 30 minutes until 6 hours had elapsed. Secondary outcome measures were perceptible and meaningful pain relief (PPR and MPR) and sensory and affective pain using the McGill Pain Questionnaire Short Form (MPQ-SF).

[0102] The NRS is an 11-point scale, with 0 representing "no pain" and 10 representing the worst pain imaginable. Rating scores of 1-4 are considered mild, 5-6 moderate, and 7-10 severe. The NRS was measured at 30-minute intervals until 6 hours had elapsed to calculate SPID6. The Pain Relief Scale (PRS) is a categorical scale showing a positive progression from "no relief," "a little relief," "some relief," "much relief" to "complete relief" (coded 0-4). TOTPAR is the area under the time-analgesic effect curve at a given time. The PRS was measured at 30-minute intervals until 6 hours had elapsed to calculate TOTPAR6. The onset of analgesia was measured using the "double stopwatch" method. After administration, two stopwatches were started simultaneously. The first stopwatch was stopped when the subject first felt perceptible pain relief (PPR). The second stopwatch was stopped when the subject felt complete pain relief, called significant pain relief (MPR).

[0103] The McGill Pain Questionnaire (MPQ), which allows subjects to describe the quality (affective domain) and intensity (sensory domain) of their pain, was completed at the start and end of the study. Participants also rated their current pain intensity (PPI) on a scale of 0 to 5. Pain intensity was assessed on a horizontal VAS ranging from 0 to 100 mm, with no pain (score 0) and worst pain (score 100) as the benchmark. TIFF2025508390000025.tif133166

[0104] There is a significant difference in LSM between treatments from 270 minutes after administration onwards.

[0105] The sum of pain intensity differences (SPID6) and area under the pain intensity effect curve (AUE6) showed significant differences at 360 minutes compared to placebo. TIFF2025508390000026.tif59166

[0106] In the cumulative responder analysis, a 61.93% improvement was observed in the treatment group compared with a 2.7% improvement in the placebo group. TIFF2025508390000027.tif95166

[0107] After 6 hours, the mean TOTPAR in the treatment group was 198 and in the placebo group was 32. After 360 minutes, there was a statistically significant difference in pain relief between the treatment and placebo groups. TIFF2025508390000028.tif78166

[0108] The mean restricted remaining time (RMST) in the treatment group was 269 minutes compared with 312 minutes in the placebo group, indicating significantly better pain relief than in the placebo group. TIFF2025508390000029.tif56166

[0109] Pain quality, as assessed by the McGill questionnaire, was analyzed using Wilcoxon tests and paired t-tests. There were significant differences in the sensory, emotional domains, and MPQ total score in the treatment group, but no significant changes in the placebo group. There were also significant differences in the VAS and PPI in the treatment group, but no significant changes in the placebo group. TIFF2025508390000030.tif166138

[0110] In conclusion, the pain-relieving formulation (treatment group) established a rapid onset of pain-relieving action in participants with acute musculoskeletal pain. The 500 mg dose of the formulation significantly improved pain intensity, with perceptible pain relief achieved just 4 hours after the start of treatment. Example 7

[0111] Efficacy of fast-acting pain-relieving preparations for menstrual pain associated with primary dysmenorrhea

[0112] This was a randomized, double-blind, placebo-controlled study in adolescent and adult female participants with primary dysmenorrhea with moderate to severe pain. Sixty eligible participants were randomized in a 1:1 ratio into two groups to receive a single dose of the fast-acting pain relief formulation or placebo (two 500 mg softgels). Prior to dosing, participants completed a baseline (immediately before dosing) 0-10 NRS menstrual pain intensity assessment.

[0113] After taking the study medication, participants completed pain / pain relief assessments (0–10 NRS and 0–4 category pain relief scale) at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, and 6 hours after administration.

[0114] Six hours after dosing, subjects completed a global assessment of their overall satisfaction with the effectiveness of the study medication.

[0115] The NRS is an 11-point scale, with 0 representing "no pain" and 10 representing the worst pain. On the 0-10 NRS scale, the rating chosen has a specific meaning with respect to the impact of pain on function. In most samples, ratings in the range of 1-4 have minimal impact on pain and can be considered to represent "mild" pain. When ratings reach 5 or 6, these ratings can be considered to represent "moderate" pain. Ratings in the range of 7-10 have the greatest impact on function and can be considered to represent "severe pain."

[0116] The pain relief scale is a categorical scale with a positive progression from "no relief" to "complete relief." TIFF2025508390000031.tif46159

[0117] Questions assessing the drug as a pain reliever 6 hours after administration or immediately after the first intake of rescue medication. TIFF2025508390000032.tif56159

[0118] The primary outcome measure was the total pain relief score (TOTPAR) using the Pain Relief Category Scale (0-4).Secondary outcomes were the total pain intensity difference (SPID) over the 6-hour study period (SPID0-6) using the 0-10 NRS, the pain intensity difference (PID) score, and the global assessment at 6 hours post-dose. TIFF2025508390000033.tif110166

[0119] SPID was calculated as the sum of the differences between pain scores over time and baseline pain scores. The sum of pain intensity differences (SPID6) showed a significant difference at 6 hours compared to the placebo group. TIFF2025508390000034.tif46166

[0120] TOTPAR was calculated as the sum of pain relief scores over a period of time using data from a 5-point categorical pain relief scale (none = 0, mild = 1, moderate = 2, good = 3, or complete pain relief = 4). TIFF2025508390000035.tif66166

[0121] The mean TOTPAR at 6 hours was 19 in the treatment group and 2 in the placebo group. There was a statistically significant difference in pain relief at 6 hours between the treatment and placebo groups.

[0122] Maximum TOTPAR percentage and maximum SPID percentage were calculated for each individual and categorized as <30%, 30-49%, 49-69%, and >70%. An individual's maximum TOTPAR was the maximum relief score obtained multiplied by the number of hours. An individual's maximum possible SPID was the initial pain rating multiplied by the number of hours the rating was recorded. Each individual's TOTPAR and SPID values ​​were converted to a maximum TOTPAR percentage and maximum SPID percentage, respectively, by dividing by the maximum calculated TOTPAR and SPID values.

[0123] 80% of participants in the treatment group were in the TOTPAR percentage category above 70% of maximum TOTPAR. In the placebo group, 66.67% of participants were below 30% of maximum TOTPAR. TIFF2025508390000036.tif58166

[0124] Six participants in the placebo group and 30 participants in the treatment group demonstrated a maximum TOTPAR of 50% or more, and the NNT for the treatment group compared with the placebo group was 1.25, indicating efficacy of the treatment.

[0125] 76.67% of participants in the treatment group had 70% or more of maximum SPID, whereas 100% of participants in the placebo group had less than 30% of maximum SPID. TIFF2025508390000037.tif43166

[0126] Global Rating Study drug efficacy 0=bad 1=Okay 2=Good 3=Very good 4=Amazing TIFF2025508390000038.tif59166

[0127] In the treatment group, 73.3% reported that the product was an excellent pain reliever, and 26.7% reported that the product was an excellent pain reliever, while in the placebo group, 83.3% reported that the product was an inadequate pain reliever. Example 8

[0128] A randomized placebo-controlled trial was conducted to analyze the efficacy of a combination of turmeric and boswellia extract in sesame oil (treatment group) compared with turmeric and boswellia extract powder (extract powder) on exercise-induced acute musculoskeletal pain. The study selected 150 healthy male and female subjects with exercise-induced acute musculoskeletal pain with pain intensity of 5 or more on the Numeric Rating Scale (NRS). Participants were divided into three groups with 50 participants in each group. Group 1 received a single dose of two 500 mg capsules of turmeric and boswellia extract in sesame oil. Group 2 received a single dose of two 500 mg capsules of turmeric and boswellia extract powder. Subjects in group 3 received two 500 mg capsules of placebo. The treatment period was 6 hours. The primary outcome in this study was the change in the sum of pain intensity differences (SPID) measured at rest. SPID is calculated from the NRS scale, an 11-point scale with 0 representing "no pain" and 10 representing the worst pain. NRS was measured at baseline and at 30-min intervals up to 6 hours after administration, at rest, during movement, and when pressure was applied to the affected area. Secondary outcome variables included total pain relief (TOTPAR), measured using a categorical scale called the Pain Relief Scale (PRS), with a positive progression from no relief to complete relief (score of 0–4). PRS responses were also measured at 30-min intervals. After administration, the onset of analgesia was measured using the double stopwatch method. TIFF2025508390000039.tif74166

[0129] The sum of the differences in pain intensity after 6 hours showed that the treatment group had a significant reduction in pain intensity at rest, pressure, and movement (SPID6rest, SPID6pres, SPID6mov) compared to the extract powder and placebo groups. TIFF2025508390000040.tif69166

[0130] The mean total pain relief after 6 hours in the treatment group was significantly better than the other two groups (TOTPAR6rest, TOTPAR6press, TOTPAR6mov). The extract powder group was significantly better than the placebo group (TOTPAR6rest, TOTPAR6press, TOTPAR6mov). At rest, compression, and movement, 98% of subjects in the treatment group reported pain relief of more than 50% of maximum TOTPAR, compared with only 6% in the placebo group. In the extract powder group, 6% reported pain relief at rest and compression, but only 2% reported pain relief of more than 50% of maximum TOTPAR during movement.

[0131] The number needed to treat (NNT) is one way of conveying the effectiveness of a treatment. NNT is the number of patients who need to be treated to prevent one bad outcome (death, stroke, etc.). A perfect NNT is 1 - everyone improves with the treatment and no one improves in the control group. A higher NNT indicates a less effective treatment.

[0132] Three participants in the placebo group and 49 participants in the treatment group achieved a maximum TOTPAR of 50% or more. Thus, the NNT for the treatment group compared with the placebo group was 1.1, again indicating efficacy of the treatment. TIFF2025508390000041.tif64166

[0133] Perceptible pain relief was 1 hour 48 minutes for the treatment group, 3 hours 54 minutes for the extract powder group, and 4 hours 12 minutes for the placebo group. The treatment group showed a highly significant treatment effect with a PPR difference of 2.2 vs. the extract powder group and 2.4 vs. the placebo group, while the extract powder group showed no significant treatment effect vs. the placebo group. Meaningful pain relief (MPR) was 2 hours 42 minutes for the treatment group, 5 hours 48 minutes for the extract powder group, and 5 hours 54 minutes for the placebo group. The test formulation showed a highly significant treatment effect with a MPR difference of 3.1 vs. the extract powder group and 3.2 vs. the placebo group, while the extract powder group showed no significant treatment effect vs. the placebo group. The treatment group achieved PPR 2.2 times faster than the extract powder group and 2.4 times faster than the placebo group. The treatment group achieved MPR 2.2 times faster than the extract powder group and the placebo group.

[0134] The above specification is illustrative and not limiting. Many variations of the disclosed compositions and processes will become apparent to those skilled in the art upon review of the specification.

Claims

1. 1. A plant-derived formulation for rapid pain relief comprising a mixture of solid turmeric extract and solid boswellia extract, said mixture loaded into an oil having a hydrophilic lipophilic balance value ranging from 10 to 19, said turmeric extract and boswellia extract being in a weight ratio of about 1:1 to 1:99, said mixture having a particle size of 200 micrometers to about 100 nanometers.

2. The mixture is a. 10 to 50% by weight of the turmeric extract; b. 1-30% by weight of the Boswellia extract, and c. Sesame oil: 40 to 90% by weight The plant-derived formulation according to claim 1 .

3. The mixture is a. about 30±2% by weight of the turmeric extract; b. about 10±2% by weight of the Boswellia extract, and c) about 60±2% by weight of said sesame oil The plant-derived formulation according to claim 2, comprising:

4. 2. The plant-derived preparation of claim 1, wherein the mixture is mixed with the oil in a weight ratio of 1:10 to 1:

1.

5. 2. The plant-derived formulation of claim 1, wherein the solid turmeric extract and the solid boswellia extract each have curcuminoids and acetyl-11-keto-beta-boswellic acid, and the ratio of the curcuminoids in the solid turmeric extract to the acetyl-11-keto-beta-boswellic acid in the solid boswellia extract is from 2:1 to 99:

1.

6. 2. The plant-derived formulation of claim 1, wherein the turmeric extract and the boswellia extract are in a weight ratio of about 2.8:1 to 3:

1.

7. 6. The plant-derived formulation of claim 5, wherein the curcuminoids are in the form of a solid turmeric extract comprising at least 80% by weight of curcuminoids and the acetyl-11-keto-beta-boswellic acid is in the form of a solid Boswellia extract comprising at least 10% by weight of acetyl-11-keto-beta-boswellic acid.

8. 6. The plant-derived formulation of claim 5, wherein the curcuminoids consist of curcumin, bisdemethoxycurcumin, and demethoxycurcumin, which are derived from turmeric rhizome, and acetyl-11-keto-beta-boswellic acid is derived from Boswellia resin.

9. The plant-derived formulation of claim 1, further comprising one or more additives and in a dosage form selected from the group consisting of soft gel capsules, capsules, pastes, ointments, drops, injections, ampoules, solutions, suspensions, emulsions, creams and oils.

10. The plant-derived formulation according to claim 9, wherein the formulation is formed into a unit dose of 500 to 2000 mg.

11. 2. The plant-derived formulation of claim 1, wherein the oil is selected from the group consisting of sesame oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, rice bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew oil, canola oil, corn oil, safflower oil, cottonseed oil, ramsey oil, niger oil, hemp oil, turmeric oil, ginger oil, animal fat, medium chain triglycerides or combinations thereof.

12. 13. A method for providing rapid pain relief in a mammal experiencing acute musculoskeletal pain by administering the plant-derived formulation of claim 1.

13. The method of claim 12, wherein the mammal is a human.

14. 13. The method of claim 12, wherein the musculoskeletal pain is exercise-induced pain, can be caused by exercise, and is selected from the group consisting of low back pain, generalized pain, muscle pain, headache, neck pain, limb pain, grade 1 sprain, joint pain, acute soft tissue injury, acute ligament injury, and acute tendon injury.

15. 13. A method for providing rapid pain relief in a mammal experiencing acute musculoskeletal pain in different body sites by administering the plant-derived preparation of claim 1.

16. 16. The method of claim 15, wherein the musculoskeletal pain is movement induced and the different body locations are head and neck, trunk, upper limbs, lower limbs and general musculoskeletal pain.

17. 13. A method for relieving menstrual pain in a mammal with primary dysmenorrhea by administering the plant-derived preparation of claim 1.

18. A method for preparing a plant-derived formulation that provides rapid pain relief by increasing oral bioavailability, comprising the steps of: a) mixing solid turmeric extract and solid boswellia extract in a weight ratio of about 2.8:1 to 3:1; b) adding the mixture to edible oil and mixing thoroughly to obtain a thick mixture; and c) The resulting mixture is passed through a bead mill several times to obtain a yellow liquid having a viscosity in the range of 270-320 mP·s.

19. 19. The method of claim 18, wherein the edible oil is selected from the group consisting of sesame oil, coconut oil, palm oil, olive oil, sunflower oil, mustard oil, lemongrass oil, rice bran oil, peanut oil, lavender oil, linseed oil, grape seed oil, almond oil, avocado oil, soybean oil, walnut oil, cashew oil, canola oil, corn oil, safflower oil, cottonseed oil, ramsey oil, niger oil, hemp oil, turmeric oil, ginger oil, animal fat, medium chain triglycerides or combinations thereof.

20. 20. The method of claim 19, wherein the edible oil is sesame oil.

21. 20. The method of claim 18, wherein an antioxidant, a combination of rosemary and green tea extract, is administered at 2000 ppm of said edible oil as a preservative.

22. 20. The process of claim 18, wherein the mixture is milled to a particle size of greater than 100 micrometers and less than 200 micrometers.

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