BACKGROUND

Anesthetics have been available for many years. For example, Lidocaine was released for commercial use in 1949 from Astra AB. Since then, it and others like it, have been used for local anesthetic, or intravenously administered for arrhythmia treatment and for acute and chronic pain conditions.

Some patients have a natural resistance to the local anesthetic effects of Lidocaine and many other amide and ester local anesthetics. Many of these patients include those with connective tissue disorders, genetic traits and various other causes that delay absorption of local anesthetics. These patients can at times, require dosages that are much larger than normal, or excessively large and in some cases risk toxicity, in order to provide a sufficient numbing effect. These patients are often frustrated with the failed attempts to achieve local anesthesia and have gone without anesthetics or have required deeper sedation to tolerate the same procedures routinely done on others with smaller doses of local anesthetics only.

Many, if not most patients complain of pain or burning with injection of the local anesthetic. This is usually due to the low pH of the anesthetic solution (which is usually very acidic) but is also to a lesser extent from the initial needle “stick”, or because of local irritation from the substrate or from the distension of the tissues associated with volume and/or barometric pressure from local injection into tissues.

Another important aspect is that anesthetics require time to take effect. Reducing the time to onset of anesthesia is particularly important when patients sustain injuries and/or require immediate or emergent pain control and treatment. Patients must endure the pain, sometimes severe, until the local anesthetic has taken effect. Typically, a narcotic or sedation or both are used first to control pain, instead of local anesthetic. Some patients require deeper anesthesia to general anesthetics to tolerate treatment of life saving or emergent treatments. Also, injectable delivery systems deliver therapeutic solutions at a large range of velocities with potentially non-uniform spatial distribution across a targeted treatment surface. Enhancing absorption rates reduces the onset time and reduces or eliminates the issues related to non-uniform distribution of therapeutic solution as well as potential irritation at the site of injection. Reducing this time to onset has been a long felt need in the area of pain management, interventions, procedures and surgery. Shortening the onset time allows a far better patient experience with improved pain control and comfort, shorter treatment time, shorter usage of facilities, equipment, providers, and staff, and an increase in patient acceptance and compliance.. Local anesthetics with shorter time to onset and depth of local anesthetics allows caregivers to proceed with procedures and other critical therapies more rapidly, safely, and comfortably for the patients.

DETAILED DESCRPTION

The solutions and methods of preparing and administering anesthetics that are presented herein include methods for enhancing the absorption rate of the anesthetic and reducing the time to onset. In one aspect, this may be achieved by increasing the pH of the Lidocaine solution. Most Lidocaine solutions are shipped from the manufacture with a lower pH of 5.0 to 7.0. In some instances, the addition of epinephrine reduces the pH to as low as 3.5.

The low pH is done to maintain the drug stability during transportation and storage. However, a very low pH relative to body tissues slows down absorption and increases patient discomfort and the probability of injection site irritation. Increasing the pH as discussed herein before injection shortens time to onset by taking advantage of the high pKa of Lidocaine. The pKa of Lidocaine is 7.8. The natural pH of the body is 7.35 to 7.45. Buffering the Lidocaine to a pH of 7.5 to 7.6 brings the solution closer to its pKa and the natural pH of the body and causes absorption that is measurable in less than 10 seconds with less pain.

The pH of the anesthetic can be elevated by addition of bases. Sodium bicarbonate (NallCCh) is a common alternative for this purpose because it is known to be safe and effective for human or animal use. Any suitable base could be used though. In another aspect, anesthetic manufacturers have used Sodium Hydroxide to adjust pH. However, elevated pH has been shown to adversely affect the stability of the drug.

Buffering Lidocaine with sodium bicarbonate is widely taught in pharmacy classes and interventional specialties to reduce pain at the injection site. However, these techniques are limited to buffering with sodium bicarbonate significantly diluted in a 10: 1 solution. The 10: 1 solution typically, only slightly reduces the burn and therefore is uncommonly used. The 10:1 solution using 1% Lidocaine and 8.4% Sodium Bicarbonate typically only elevates the pH of Lidocaine to 7.25 or 7.3.

However, as the pKa of Lidocaine is 7.8, further elevation of the will facilitate more rapid absorption with less pain. If a pH of 7.5 or higher is used with Lidocaine, the time of onset drops from 2-5 minutes to less than or equal to 10 seconds. Clinical experience using the method of the present disclosure has shown that in fact onset often occurs in as little as 5 seconds. This advantageously allows clinicians to effectively administer Lidocaine and minimize patient discomfort without requiring a pause in the procedure to wait for the anesthetic to take effect. Buffering the Lidocaine with sodium bicarbonate according to the present disclosure may also reduce the depth of the anesthetic slightly, but more significantly, it may also reduce the duration of the anesthetic affect from 2-4 hours to 40-60minutes, significantly affected by dilution. Thus full feeling and function may return more rapidly with the buffering techniques of the present disclosure as opposed to the conventional approach. When deeper anesthesia or longer duration is desired, one can used increased concentration of the anesthetic, ie 2% Lidocaine, instead of 1% Lidocaine.

In another example, Bupivacaine is often manufactured and distributed with a pH of about 6.3 and typically has a time to onset of 4-15 minutes. Clinical experience using the methods of the present disclosure shows that buffering Bupivacaine to increase the pH to 6.5 to 7. 1 , which is closer to the pKa of 8. 1 , reduces the time to onset of Bupivacaine (0.5% concentration ) to less than 30 seconds. With Bupivacaine buffered in this way, the depth of anesthetic is faster to onset, deeper, and the duration of anesthetic is generally unchanged.

In one example, a Radio Frequency Ablation (RFA) procedure requires a nerve to be burned at 80 degrees Celsius for 60-120 seconds which causes considerable pain. Such a procedure is typically performed in an Ambulatory Surgery Center (ASC) where Intravenous (IV) sedation is available. Using the methods of the present disclosure, the procedure can be performed in a doctor’s office or other outpatient clinical setting without IV sedation using 1% Lidocaine buffered to pH of about 7.55 or 0.5% Bupivacaine buffered to a pH of 6.5 to 7.1 . Patient comfort is increased significantly using the techniques of the present disclosure which advantageously makes RFA a more attractive option for patients and clinicians.

In another example, clinical experience using the methods of the present disclosure indicates that prior to applying the buffering techniques of the present disclosure, 50% of Lumbar cases, and 70% of Cervical cases required heavy sedation in the ASC. Using the techniques of buffered Lidocaine and Bupivacaine in the present disclosure, only 10% of Lumbar cases and 20% of Cervical cases were sent to the ASC. In many instances, 95% of Lumbar cases, and 90% of Cervical cases are performed in the office using the buffering techniques of the present disclosure. Additional results for buffering Lidocaine are summarized in the following Table 1 :

In another example, 5 ml of Lidocaine HCL at a 2% concentration with a pH of 6.06 was buffered using 5 ml of sodium bicarbonate at an 8.4% concentration in sterile water for 10 ml anesthetic composition of the present disclosure. The resulting pH was measured to be 7.69-7.7. No precipitate or cloudiness was noticed upon visual inspection of the resulting composition. The pH meter used in this example was a pH monitor obtained commercially from American Marine Inc. that was calibrated at 70 degrees F against known compounds with a pH of 7.000 yielding a pH of 7.00 on the meter, and again by a known compound with a pH of 10.000 yielding a measure pH of 10.00 on the meter.

In another example. Lidocaine HCL with a 1 % concentration that also included Epinephrine at a ratio of 1 :100,000 was buffered according to the present disclosure using sodium bicarbonate at an 8.4% concentration with the results as shown below in Table 2:

The above dilutions shown in Table 2 illustrate that the pH of the commonly quoted 10: 1 solutions used to reduce the injection site pain or burn fail to achieve the required pH for Lidocaine (pH 7.45 to 7.7) of the present disclosure and thus fail to affect the onset of the local anesthetic. A typical 10:1 solution only produces a pH of 7.10 for Lidocaine with Epinephrine and thus do not exhibit the benefits of decreased time to onset and reduced pain discussed herein.

In another example, Lidocaine HCL with a 1 % concentration was buffered according to the present disclosure using sodium bicarbonate at an 8.4% concentration in sterile water with the results as shown below in Table 3 :

In another example, Bupivacaine PF at a 0.5% concentration was buffered using two different buffering agent mixtures that each included a 9: 1 mixture of 9ml of Sodium Chloride at a 0.9% concentration and 1ml of Sodium Bicarbonate at a 8.4% concentration. The results are shown below in Table 4:

Note that specimen #5 in Table 4 was clear initially, then some wisps with particles were seen. However, after about 10 min, the solution was observed to be cloudy with no particles seen. In another example, Bupivacaine MPF at a 0.75% concentration was buffered using the same two different buffering agent mixtures mentioned above with respect to Table 4. The results are shown below in Table 5:

In another example, Ropivacain (Naropin) at a 0.5% concentration was buffered using the same two different buffering agent mixtures mentioned above with respect to Tables 4 and 5. The results are shown below in Table 6:

It is notable that in this last example, specimen 1 was observed to be faintly cloudy after 2 minutes, and specimen 2 was faintly cloudy after 3 minutes. Based on the above findings, at least some of the anesthetic compounds tested, such as Lidocaine, when mixed with Epinephrine, showed no precipitation at the highest pH value in the buffered solution.

In another example, Lidocaine HCL with a 1% concentration was buffered according to the principles of the present disclosure with the results shown in Table 7:

In another example, Lidocaine HCL with a 1% concentration that also included Epinephrine at a ratio of 1 :100,000 MDV was buffered according to the present disclosure using sodium bicarbonate with the results as shown below in Table 8: In another example, Bupivacaine HCL with a 0.5% concentration that also included Epinephrine at a ratio of 1 :100,000 PF was buffered according to the present disclosure using sodium bicarbonate with the results as shown below in Table 9:

In another example, Bupivacaine with a 0.5% concentration buffered according to the present disclosure using sodium bicarbonate with the results as shown below in Table 10:

Accordingly, the disclosed method optionally includes preparing an anesthetic composition that includes an anesthetic compound suitable for injection into humans or animals. The pH of the anesthetic compound may optionally be measured prior to adding a buffering agent. A buffering agent may be added to the anesthetic compound to adjust the pH of the resulting anesthetic composition. For example, the buffering agent may be injected into a vial with the anesthetic compound to create the resulting composition.

In another aspect, adding the buffering compound adjusts (usually increases) pH of the anesthetic composition. The resulting pH may be greater than 7.0, greater than 7.35, greater than 7.5, and/or less than 8.0 for some anesthetics such as Lidocaine. In one example, the pH of Lidocaine is adjusted upward to 7.55. In another example, the pH of Bupivacaine is adjusted (updward) to 6.95.

In another aspect, the anesthetic compound may define an initial pH that is less than 7.3, or less than 3.1 , or between 2.4 and 7.0 prior to adding the buffering solution. In another aspect, the buffering solution is predominately Sodium Bicarbonate (NaHCO3).

Once buffered, the resulting anesthetic compound may be drawn from the vial or other container using a hypodermic needle or other similar instrument and injected at the preferred location. Any suitable approach for subcutaneous injection of liquids may be used to introduce the buffered anesthetic compound according to the present disclosure into the area to be affected.

In another aspect, the method optionally includes determining the time to onset after the injection of the anesthetic composition. Complete sensory block may be determined by applying a pointed instrument to the affected area to determine when the patient loses sensory response. This usually occurs, with the present method, at less than 35 seconds for slower acting anesthetics like Bupivacaine, or perhaps is less than 10 seconds for faster acting compounds like Lidocaine.

In one example, the principles of the present disclosure were applied in the case of Jane Doe, a 56-year-old female with Ehlers-Danlos Syndrome (EDS) and a known resistance to numerous prior attempts at the application of local anesthetics. EDS is a hereditary connective tissue disorder that manifests clinically with skin hyperelasticity, hypermobility of joints, atrophic scarring, and fragility of blood vessels. Jane Doe had previously never experienced local anesthesia effect from any local anesthetic administration. This includes multiple attempts with dental care and with medical interventions, procedures or surgeries. Jane Doe was able to experience the beneficial effects of the anesthetic prepared according to the present disclosure in less than 30 seconds after administration. Jane Doe had, up to that time, never been able to enjoy the effects of local anesthetic.

In another example, the principles of the present disclosure have been successfully applied in an out-patient clinical setting to reduce pain from procedures such as radio frequency ablations. In the case of John Doe, the principles of the present disclosure were used on a 42-year-old white male with a longstanding history of lumbar spondylosis that failed to respond to normal conservative pain management. It was recommended that the patient undergo radiofrequency ablation. John Doe had previously experienced difficulty tolerating any procedures in the office due to sensitivity to pain and the resulting anxiety. He requested that we attempt this in the office with the first radiofrequency ablation on the left side. Procedure was performed with pH adjusted Bupivacaine of the present disclosure and the patient noted good pain control within 30 seconds of administration. Past experience with Bupivacaine shows that it typically takes 4-15min to take effect. John Doe enjoyed good pain control for 5 hours with pH adjusted Bupivacaine according to the present disclosure that then tapered off after 24 hours.

The concepts illustrated and disclosed herein are further illustrated by the following non-limiting numbered examples:

1. A method of preparing an anesthetic composition, comprising, obtaining or preparing an aesthetic compound.

2. The method of any other example, comprising, measuring the pH of the anesthetic compound, optionally, prior to adding a buffering agent.

3. The method of any other example, comprising, adding a buffering agent to an anesthetic to adjust the pH of the resulting anesthetic composition.

4. The method of any other example, comprising, adjusting the pH of the anesthetic composition to greater than 7.35.

5. The method of any other example, comprising, adjusting the pH of the anesthetic composition to less than 8.0.

6. The method of any other example, comprising, measuring the pH of the anesthetic composition, optionally, after adding a buffering agent.

7. The method of any other example, comprising, increasing the pH of the anesthetic composition to between 7.34 and 8. 1.

8. The method of any other example, wherein the anesthetic is arranged and configured for injection into a human or animal subject.

9. The method of any other example, wherein the anesthetic compound defines an initial pH that is less than 7.3 prior to adding the buffering solution.

10. The method of any other example, wherein the anesthetic compound defines an initial pH that is less than 3.1 prior to adding the buffering solution. 11. The method of any other example, wherein the anesthetic has an initial pH of 2.4 to 7.0 prior to adding the buffering agent.

12. The method of any other example, wherein the buffering solution is predominately Sodium Bicarbonate (NaHCCh).

13. The method of any other example, wherein the anesthetic compound is a local anesthetic.

14. The method of any other example, wherein the anesthetic includes Lidocaine 1%.

15. The method of any other example, wherein the anesthetic includes Bupivacaine 0.5%.

16. The method of any other example, wherein the buffering agent or solution includes NaHCO ₃ at a concentration of 8.4% by weight.

17. The method of any other example, wherein the anesthetic has an initial pH of 6.9 or less prior to adding the buffering agent.

18. The method of any other example, wherein the anesthetic has a concentration of less than 2.2% by weight.

19. The method of any other example, wherein the anesthetic has a concentration of between 0.5% and 2.2% by weight.

20. The method of any other example, comprising, adding a buffering agent to an anesthetic to increase the pH of the anesthetic composition to approach or achieve a pH that is at or above the pKa of the anesthetic compound.

21. The method of any other example, comprising, determining the time to onset.

22. The method of any other example, comprising, determining when complete sensory block in the affected injection area is achieved.

23. The method of any other example, wherein the time to onset is less than 10 seconds.

24. The method of any other example, wherein the time to onset is less than 35 seconds.

Glossary of Definitions and Alternatives

While the invention is illustrated in the drawings and described herein, this disclosure is to be considered as illustrative and not restrictive in character. The present disclosure is exemplary in nature and all changes, equivalents, and modifications that come within the spirit of the invention are included. The detailed description is included herein to discuss aspects of the examples illustrated in the drawings for the purpose of promoting an understanding of the principles of the invention. No limitation of the scope of the invention is thereby intended. Any alterations and further modifications in the described examples, and any further applications of the principles described herein are contemplated as would normally occur to one skilled in the art to which the invention relates. Some examples are disclosed in detail, however some features that may not be relevant may have been left out for the sake of clarity.

Where there are references to publications, patents, and patent applications cited herein, they are understood to be incorporated by reference as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference and set forth in its entirety herein.

Singular forms “a”, “an”, “the”, and the like include plural referents unless expressly discussed otherwise. As an illustration, references to “a device” or “the device” include one or more of such devices and equivalents thereof.

Directional terms, such as "up", "down", "top" "bottom", "fore", "aft", "lateral", "longitudinal", "radial", "circumferential", etc., are used herein solely for the convenience of the reader in order to aid in the reader’s understanding of the illustrated examples. The use of these directional terms does not in any maimer limit the described, illustrated, and/or claimed features to a specific direction and/or orientation.

Multiple related items illustrated in the drawings with the same part number which are differentiated by a letter for separate individual instances, may be referred to generally by a distinguishable portion of the full name, and/or by the number alone. For example, if multiple “laterally extending elements” 90A, 90B, 90C, and 90D are illustrated in the drawings, the disclosure may refer to these as “laterally extending elements 90A-90D,” or as “laterally extending elements 90,” or by a distinguishable portion of the full name such as “elements 90”.

The language used in the disclosure are presumed to have only their plain and ordinary meaning, except as explicitly defined below. The words used in the definitions included herein are to only have their plain and ordinary meaning. Such plain and ordinary meaning is inclusive of all consistent dictionary definitions from the most recently published Webster’s and Random House dictionaries. As used herein, the following definitions apply to the following terms or to common variations thereof (e.g., singular/plural forms, past/present tenses, etc.): “About” with reference to numerical values generally refers to plus or minus 10% of the stated value. For example, if the stated value is 4.375, then use of the term “about 4.375” generally means a range between 3.9375 and 4.8125.

“Acid” generally refers to a chemical that donates protons or hydrogen ions and/or accepts electrons. Most acids contain a hydrogen atom bonded that can release (dissociate) to yield a cation and an anion in water. The higher the concentration of hydrogen ions produced by an acid, the higher its acidity and the lower the pH of the solution.

An acid may be defined in different ways:

Arrhenius Acid: By this definition, an acid is a substance that increases the concentration of hydronium ions (H3O+) when added to water, or increases the concentration of hydrogen ion (H+) as an alternative.

Brunsted-Lowry Acid: By this definition, an acid is a material capable of acting as a proton donor. This is a less restrictive definition because solvents besides water are not excluded. Essentially, any compound that can be deprotonated is a Bronsted-Lowry acid, including typical acids, plus amines, and alcohol. This is the most widely used definition of an acid.

Lewis Acid: A Lewis acid is a compound that can accept an electron pair to form a covalent bond. By this definition, some compounds that don't contain hydrogen qualify as acids, including aluminum trichloride and boron trifluoride. In general, acids turn litmus paper from blue to red, has a sour taste (e.g. vinegar), creates a burning sensation on human tissue, may be sticky to the touch, and reacts with metals to produce hydrogen gas.

Acids may be identified as either strong or weak based on how completely they dissociate into their ions in water. A strong acid, such as hydrochloric acid, completely dissociates into its ions in water. A weak acid only partly dissociates into its ions, so the solution contains water, ions, and the acid (e.g., acetic acid).

In terms of pH, an “acidic” solution has a pH that is less than7.

“Activate” generally is synonymous with “providing power to”, or refers to “enabling a specific function” of a circuit or electronic device that already has power. “Anesthetic” generally refers to a substance that results in a temporary loss of sensation or awareness, and/or induces insensitivity to pain. A “local” anesthetic causes a reversible loss of sensation for a limited region of the body without affecting consciousness, while a “general” anesthetic causes a reversible loss of consciousness. Examples of general anesthetics include, but are not limited to, inhaled anesthetic agents such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, or xenon; and intravenous anesthetic agents such as amobarbital, methohexital, thiamylal, thiopental, benzodiazepines, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, sufentanil, buprenorphine, butorphanol, diamorphine, hydromorphone, levorphanol, pethidine (also called meperidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine. Examples of local anesthetics include, but are not limited to, Lidocaine, prilocaine, Bupivacaine, levoBupivacaine, ropivacaine, mepivacaine, dibucaine and etidocaine, mepivacaine, procaine, benzocaine, cocaine, butacaine, tetracaine, isocaine, proparacaine, metabutoxycaine, pyrocaine, , piridocaine, and eucaine. Anesthetics can be further divided into “Amide” and “Ester” anesthetics. Properties of some non-limiting examples of amide anesthetics are shown in Table 1 1 below: Properties of some non-limiting examples of ester anesthetics are shown in Table 12 below:

“And/or” is inclusive here, meaning “and” as well as “or”. For example, “P and/or Q” encompasses, P, Q, and P with Q; and, such “P and/or Q” may include other elements as well.

“Base” generally refers to a chemical that donates electrons, accepts protons, or releases hydroxide (OH-) ions in aqueous solution. Bases display certain characteristic properties that can be used to help identify them. Bases tend to be slippery to the touch (e.g., soap), may taste bitter, react with acids to form salts, and catalyze certain reactions. Types of bases include Arrhenius base, Bronsted-Lowry base, and Lewis base. Examples of bases include alkali metal hydroxides, alkaline earth metal hydroxides, and soap.

Strong bases and concentrated bases are caustic in that they react vigorously with acids and organic matter. Bases also react in predictable ways with pH indicators. A base turns litmus paper blue, methyl orange yellow, and phenolphthalein pink. Bromothymol blue remains blue in the presence of a base. In terms of pH, a “basic” solution has a pH greater than 7.

“Complete Sensory Block” is generally referred to a loss of nerve sensation in response to stimulation by a needle, pin, or other pointed object.

“Multiple” as used herein is synonymous with the term “plurality” and refers to more than one, or by extension, two or more.

“Optionally” as used herein means discretionary; not required; possible, but not compulsory; left to personal choice.

“pKa” generally refers to a number that describes the acid strength of a particular molecule. This value provides a measurement of the strength of an acid according to how tightly a proton is held by a Bronsted acid. The lower the value of pKa, the stronger the acid and the greater its ability to donate its protons. In another aspect, pKa is equal to the - logioKa.

“Portion” means a part of a whole, either separated from or integrated with it.

“Predominately” as used herein is synonymous with greater than 50%.

“Time to onset” generally refers to the time interval between the end of total local anesthetic administration and complete sensory block.