Compositions for treatment of refractory painful disc-related conditions and methods for delivery thereof to treat such conditions

Abstract

The present application discloses a composition for treating painful disc injury syndrome (PDDS), disc bulging, disc herniation, and disc herniation, as well as a delivery method and recommended treatment regimen for delivering an effective dose of the composition to a patient. The composition has the characteristics of inflammation resistance, oxidation resistance, vasodilation and spasmolysis. The composition is administered by intravenous drip over a specific period of time to relieve pain.

Description

Technical Field

[0001] This application relates to the treatment of refractory disc-related syndromes and conditions, collectively known as Painful Damaged Disc Syndrome (PDDS), including disc protrusion, bulge, and herniation. More specifically, this application discloses a pharmaceutical composition, its delivery method, and recommended treatment regimen to address pain associated with PDDS, while the patient's remaining treatment options are spinal epidural injection or spinal surgery. Background Technology

[0002] The human spine consists of 33 vertebrae, with intervertebral discs between each vertebra to provide cushioning—acting as shock absorbers (see...). Figure 1 ).

[0003] The intervertebral disc consists of an outer layer called the annulus fibrosus, a dense ring of collagen that surrounds the gelatinous portion inside the disc, the nucleus pulposus (see also: Figure 1 ).

[0004] PDDS is used to describe all types of intervertebral disc lesions—including but not limited to disc bulging, prolapse, herniation, and herniation—that can cause spinal pain and symptoms, with or without radiculopathy. In cases of disc bulging, prolapse, and herniation, the outer annulus fibrosus bulges outward. Disc herniation occurs when part or all of the internal nucleus pulposus protrudes outward through the annulus fibrosus (see [link to PDDS]). Figure 1 ).

[0005] The pathophysiology of intervertebral disc disease is considered to be the result of a combination of mechanical compression of the spinal cord by the intervertebral disc and a local increase in inflammatory material around the spinal nerve roots (1,2,3). There is evidence that a specific inflammatory molecule called tumor necrosis factor-α is released in damaged, degenerated intervertebral discs (1,4).

[0006] The most common cause of PDDS is a degenerative process, where the intervertebral discs lose water content and become more fragile as people age. This process leads to progressive disc degeneration, causing chronic spinal pain that often radiates to the arms and legs.

[0007] The second most common cause of PDDS is trauma. In this case, the patient is likely to recall the pathogenic injury event, usually caused by lifting or twisting.

[0008] Intervertebral disc disease is a potential cause of back pain in less than 5% of patients (5). The annual incidence of disc herniation is approximately 5–20 cases per 1,000 adults, most commonly in the 30–50 age group, with a male-to-female ratio of 2:1 (5). In the United States, lumbar disc herniation alone affects more than 3 million people annually.

[0009] 85-90% of patients with pain / symptoms related to intervertebral disc disease will experience relief within 8-12 weeks, regardless of whether they receive treatment. Several common treatment methods can be used to address pain associated with intervertebral disc injury / disease. These treatments include, for example, massage, physical therapy, acupuncture, and chiropractic, as well as medications such as ibuprofen, naproxen, aspirin, and acetaminophen.

[0010] PDDS is often very painful, and for some patients, these treatments have proven ineffective. Unfortunately, for those with refractory pain, effective conservative treatment options are very limited. Currently, the remaining options are continued use of analgesics, interventional treatments, or surgical repair.

[0011] The serious consequence of prolonged use of painkillers is addiction, while there is limited evidence for the use of muscle relaxants (such as cyclobenzaline) or oral steroids (6).

[0012] Epidural corticosteroid injections provide mild, questionable short-term improvement, but do not provide long-term relief (7). Evidence is limited that epidural injections are effective for more than 3 months, and repeat injections are usually required (8,9).

[0013] For these refractory patients, the last resort is spinal surgery (discentrectomy or laminectomy) or spinal fusion. The benefits of surgical intervention are moderate and tend to diminish over time postoperatively. Some patients require repeat surgery. Studies have shown that 5–7% of patients who have undergone discectomy require additional discectomy (10).

[0014] Studies have shown that primary lumbar discectomy is statistically associated with an increased likelihood of future lumbar fusion (a more invasive procedure). The incidence of additional surgery due to disc herniation at the same level is approximately 6%, and 22-25% of patients who have undergone surgery experience persistent chronic pain. Although serious complications from surgery or interventional treatments are rare, cases of paralysis and death have been reported in the literature.

[0015] Patients with chronic, refractory PDDS require alternative treatment options beyond invasive procedures or surgery. The outcomes of these procedures are uncertain. This invention addresses this need by providing a non-invasive, non-addictive, and effective method of pain relief that addresses the root cause of pain, unlike any currently available treatment. Summary of the Invention

[0016] In a first aspect of the invention, a pharmaceutical composition comprising magnesium chloride and colchicine is disclosed. This composition possesses vasodilatory, antispasmodic, anti-inflammatory, and antioxidant properties, which synergistically alleviate pain in patients suffering from chronic, refractory spinal pain (with or without radiculopathy). (See recommended methods for details.) Figure 4 ).

[0017] The composition is in liquid form and is soluble in 50 cc of normal saline. In the first aspect, the composition exerts its therapeutic effect when directly released into the patient's vein. The composition is administered via intravenous infusion over a period of more than 20-30 minutes.

[0018] In one embodiment, the composition is infused 13-15 times over a 13-15 week treatment course. In another aspect, multiple treatments may be provided periodically or at fixed intervals.

[0019] In a preferred embodiment, the composition comprising 1000 mg magnesium chloride and 1.0 mg colchicine is administered via intravenous "infusion" over a period of more than 20-30 minutes, for 13-15 treatment cycles, twice weekly for 3 weeks.

[0020] This is the standard care regimen for most patients with chronic pain caused by PDDS.

[0021] In an alternative embodiment, the dosage range of colchicine in the composition is variable (0.5-1.0 mg), while the dosage of magnesium remains constant. In this respect, the dosage depends on the patient's age, GFR range / CrCL ( Figure 3 The response to treatment and the skill level of the medical practitioner should also be considered. Furthermore, potential medical conditions and medication use should be taken into account.

[0022] In alternative implementations, the number and frequency of treatments required to achieve effective and lasting pain relief are variable, depending on the patient's age, GFR / CrCL level, and underlying conditions. Figure 3 Treatment response and judgment by those skilled in the art.

[0023] In an alternative implementation, the composition is administered via intravenous infusion in a single treatment, in combination with analgesics, to initiate immediate treatment of acute / severe pain, and followed by instructions for subsequent care.

[0024] On the other hand, patients with spondyloarthritis will benefit from the anti-inflammatory properties of the composition, thereby relieving pain.

[0025] On another front, the composition is able to alleviate broad-spectrum inflammation. This is evidenced by the reduction in serum inflammatory markers.

[0026] This invention may be implemented in various ways. The foregoing exemplary embodiments are intended to illustrate, rather than limit, the breadth and depth of embodiments that may fall within the scope of the appended and future claims, which define the invention.

[0027] In another embodiment, the composition is administered to the patient multiple times via intravenous infusion to reduce or eliminate pain. In this embodiment, the number of treatments may be performed sequentially. In an alternative embodiment, the number of treatments is based on effective pain relief.

[0028] In some embodiments, the dosage range of the composition in each treatment is variable.

[0029] In an alternative embodiment, the dosage range of the composition remains constant during each treatment.

[0030] In this respect, the dosage / use range of the composition depends on the intensity of the patient's inflammatory pain, age, and GFR range ( Figure 3 ).

[0031] In this embodiment of the application, the patient should not receive a dose of a composition containing more than 1 mg of colchicine in any single treatment.

[0032] In this embodiment of the application, patients should not receive a dose of the composition containing 2 mg of colchicine during any 7-day cycle.

[0033] In another claim, it is noted that there is no specific agent specifically developed for treating chronic, intractable pain caused by intervertebral disc injury or disease. Attached Figure Description

[0034] The accompanying drawings illustrate embodiments and are used to explain the principles of the disclosed embodiments. However, it should be understood that these drawings are for illustrative purposes only and are not intended to limit the scope of the related applications.

[0035] Figure 1 A schematic diagram of an organism is shown, illustrating the various parts of the spine.

[0036] Figure 2 A graph shows the loss of colchicine analog AC bound to tubulin over time, in the absence or presence of magnesium chloride.

[0037] Figure 3 A graph showing how the normal GFR range changes with patient age is presented. Furthermore, the various stages of kidney disease and recommended dose adjustments based on the GFR range are outlined.

[0038] Figure 4 The chemical structure of colchicine is shown.

[0039] Figure 5 The chemical structure of magnesium chloride is shown.

[0040] Figure 6 A flowchart illustrating the methods for providing treatment to people with PDDS is shown. Detailed Implementation

[0041] To facilitate understanding of the principles of the present invention, reference is made to the exemplary embodiments shown in the accompanying drawings, and the invention is described using specific language. However, it should be understood that this does not imply any limitation on the scope of the invention. Any changes and further modifications made by those skilled in the art to the features of the invention shown herein, as well as any other applications of the principles of the invention shown herein, after understanding the contents of this disclosure, should be considered to fall within the protection scope of the invention.

[0042] The term "intravenous," hereinafter abbreviated as "IV," defines the route of administration of the disclosed composition. This route of administration involves administering the composition directly into a vein. This process is performed by "infusion," rather than injection. This route of administration of the present invention optimizes the synergistic effect of magnesium chloride and colchicine.

[0043] The term "radiculopathy" refers to diseases of the nerve roots, such as nerve compression, which can cause symptoms in the limbs.

[0044] The term "muscle spasm" refers to chronically high-tension, tense muscles.

[0045] The term "vertebral musculature" refers to the muscles of the spine.

[0046] The term "tubulin" in this article refers to the building blocks of microtubules, which are narrow, hollow tubular structures within cells.

[0047] The term "mitosis" in this article refers to a type of cell division that results in the production of two daughter cells, each with the same number and type of chromosomes as the parent cell's nucleus.

[0048] The term "half-life" (hereinafter also referred to as "t½") refers to the time period required for the concentration or content of a drug in the blood to decrease by half.

[0049] This application relates to a pharmaceutical composition comprising colchicine and magnesium chloride. The composition has anti-inflammatory, antioxidant, antispasmodic, and vasodilatory properties, and can relieve / eliminate pain in patients with PDDS. When the intervertebral disc is damaged or diseased, inflammation occurs, which is the source of most of the pain felt by patients with PDDS.

[0050] The anti-inflammatory agents in this invention are magnesium chloride and colchicine (see [link]). Figure 4 and Figure 5 ).

[0051] Magnesium is known to have anti-inflammatory properties. 50% of the US population is magnesium deficient, and when magnesium levels are low, intracellular calcium ion (Ca++) levels rise, triggering the release of various calcium-activated pro-inflammatory substances. Magnesium supplementation can prevent the influx of intracellular ions, thereby preventing the release of various pro-inflammatory substances (11) (see [link to article]). Figure 5 ).

[0052] Colchicine is known to have anti-inflammatory properties. The anti-inflammatory properties of colchicine lie in its ability to bind to tubulin via the tubulin-colchicine binding complex, thereby inhibiting cell division (mitosis) and blocking the formation of various subsequent pro-inflammatory substances (12) (see [link to article]). Figure 4 ).

[0053] Magnesium, when administered concurrently with colchicine, enhances the anti-inflammatory properties of colchicine. The anti-inflammatory properties of colchicine stem from its ability to bind to the colchicine-tubulin binding complex (13). The longer the colchicine binds, the more significant its anti-inflammatory effect. Adding magnesium to colchicine reduces its dissociation rate by several times, prolonging its half-life from 4-10 hours, thereby enhancing its anti-inflammatory potential (see [link to article]). Figure 2 , 4 、5)(13).

[0054] The synergistic anti-inflammatory properties of these agents in this invention make them effective, unique, and novel in relieving pain.

[0055] Magnesium enhances the ability of colchicine to bind to tubulin, which is a key component in understanding the effectiveness and uniqueness of this invention.

[0056] An integral part of tissue damage, including intervertebral disc damage, is oxidative pathology or oxidative stress. Colchicine has antioxidant properties (14). The role of magnesium as an antioxidant is well-established (15).

[0057] The synergistic antioxidant properties of this invention help make the composition effective, unique, and novel.

[0058] It is well known that intervertebral discs have poor blood supply. Due to this poor blood supply, intervertebral discs are known for their slow healing. Magnesium has a vasodilatory effect due to its effects on smooth muscle, and this effect becomes pronounced and immediate after intravenous administration. Vasodilation enhances blood circulation throughout the body, including to the intervertebral disc. Simultaneous intravenous administration of magnesium chloride and colchicine allows colchicine to penetrate more easily and act on the damaged, inflamed area of ​​the intervertebral disc for a longer period.

[0059] The pain in PDDS originates from inflammation of the intervertebral discs and spasm of the spinal muscles. This invention possesses pain-relieving properties in the treatment of PDDS. The pain-relieving components in this invention are magnesium chloride and colchicine.

[0060] Colchicine can target the inflammatory components of pain, as can magnesium.

[0061] Magnesium can relieve spinal muscle spasms—a component of pain associated with PDDS—through its antispasmodic effect on skeletal muscle tissue.

[0062] By simultaneously addressing inflammation and muscle spasms in patients with PDDS, the composition provides effective pain relief without the need for potentially addictive analgesics.

[0063] In its implementation, this disclosure discloses a method such as Figure 6 The method 600 shown is for treating a patient with PDDS. The method includes multiple steps, the order of which may be provided as an example only to enable those skilled in the art to understand the invention. The method includes selecting a patient for treatment based on the fact that he / she has experienced chronic or acute pain for more than 3 months; subsequently, a medical history and physical examination, including blood tests and radiographic imaging, are performed. Such examinations include: a. Past and present medical history; b. Past and current medication history; c. Blood tests include differential CBC and platelet count, liver function, kidney function, and electrolyte balance.

[0064] The method further includes treating the patient if radiographic evidence of PDDS is present and blood tests are acceptable. The patient then begins treatment. Subsequently, an intravenous infusion bag containing the composition is prepared within 2 hours of the patient's arrival, and the patient's consent is obtained before catheter insertion. The patient must be adequately rehydrated before treatment, and the dosage may remain constant throughout each treatment.

[0065] The method further involves inserting and securing an intravenous catheter to prevent accidental leakage or extravasation of magnesium into the subcutaneous tissue. This is to ensure that chemical burns do not occur. (Intravenous bolus injections via needles or butterfly catheters are not recommended, as this may increase the risk of chemical burns). The treatment plan is then initiated immediately after the first treatment and followed as closely as possible, based on the patient's outcomes and needs. Treatment depends on the physician's assessment of the patient's needs.

[0066] This invention may be implemented in various ways. The foregoing exemplary embodiments are intended to illustrate, and not limit, the breadth and depth of embodiments that may fall within the scope of the appended and future claims, which define the invention.

Claims

1. A pharmaceutical composition comprising at least 1 mg of colchicine as an anti-inflammatory agent and 1000 mg of magnesium chloride as an antioxidant, vasodilator, antispasmodic agent and anti-inflammatory agent.

2. The composition according to claim 1, wherein the anti-inflammatory agent is colchicine.

3. The composition according to claim 1, wherein the antioxidant, vasodilator, anti-inflammatory agent and antispasmodic agent are magnesium chloride.

4. The composition according to claim 1, wherein the composition further comprises at least 50 cc of physiological saline.

5. The composition of claim 1, wherein the composition is released directly into the patient's vein via "infusion".

6. The composition according to claim 1, wherein the composition is in liquid form.

7. The composition according to claim 1, wherein the composition comprises 0.5-1 g colchicine and 1000 mg magnesium chloride, and is released in a controlled amount not exceeding 57 cc within 10-30 minutes, to effectively treat pain and intractable pain associated with intervertebral disc disease.

8. The composition of claim 2, wherein the composition is administered to the patient by intravenous infusion in at least one treatment to initiate effective treatment and subsequently provide guidance for further treatment.

9. The composition of claim 3, wherein the composition is administered to a patient via intravenous infusion in a series of treatments to provide effective treatment for pain and intractable pain associated with intervertebral disc disease.

10. The composition of claim 4, wherein the number of treatments providing effective treatment to eliminate one or more types of pain and intractable pain associated with intervertebral disc disease depends on the intensity of the patient's inflammatory pain.

11. The composition of claim 5, wherein the dosage range of the composition, administered directly to a patient's vein via infusion, is variable in each treatment session.

12. The composition of claim 6, wherein the dosage range of the composition remains constant in each treatment.

13. The composition according to any one of the preceding claims, wherein, The dosage / use range of the composition, delivered directly to the patient's vein via infusion, depends on the individual patient's age and GFR range, as well as pain and intractable pain associated with disc disease, including painful disc injury syndrome (PDDS), which includes disc bulging, herniation, and herniation, causing spinal pain symptoms with or without radiculopathy.

14. The composition of claim 7, wherein the number of treatments providing effective treatment to eliminate one or more types of pain and intractable pain associated with intervertebral disc disease depends on the intensity of the patient's inflammatory pain.

15. The composition of claim 8, wherein the dosage range of the composition in each treatment is variable and is assessed by a medical practitioner based on the individual's basic condition.

16. The composition of claim 9, wherein the dosage range of the composition remains constant in each treatment according to the recommended regimen.

17. A method of providing treatment to a patient diagnosed with PDDS, the method comprising: Patients are selected for treatment based on the fact that they have experienced chronic or acute pain for more than 3 months; A medical history and physical examination are performed, including blood tests and radiographic imaging to include past and present medical history and past and present medications; the blood tests include classified CBC and platelet counts, liver function, kidney function and electrolyte balance; If there is radiographic evidence of PDDS and blood tests are acceptable, the patient will be treated. The patient is treated through multiple steps, the steps of which further include: Within 2 hours of the patient's arrival, prepare an intravenous infusion bag containing the composition, which includes at least 1 mg of colchicine as an anti-inflammatory agent and 1000 mg of magnesium chloride as an antioxidant, vasodilator, antispasmodic and anti-inflammatory agent. Obtain the patient's consent before inserting the catheter; Insert and secure the intravenous infusion tubing to prevent accidental magnesium leakage or extravasation into the subcutaneous tissue; and The treatment plan should begin immediately after the first treatment, and the patient should be monitored as closely as possible based on their outcomes and needs.

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