Process for Manufacturing Stable Epinephrine

Abstract

Epinephrine formulated in aqueous solvent at a basic pH of about 8.5 remains in solid state. My data show that epinephrine formulated at a pH of about 8.5 is surprisingly resistant to oxidation. I here teach how to formulate solid-state epinephrine in basic solution, and how to use solid-state epinephrine to make pharmaceutical dosage forms.

Claims

1. A process for manufacturing a solid-state epinephrine pharmaceutical dosage form, the process comprising: mixing epinephrine in an aqueous solvent and at least one basic-pH excipient to produce a mixture having a pH of about 8.5, whereby the epinephrine remains in solid state.

2. The process of claim 1, said mixture substantially free of antioxidant.

3. The process of claim 1, said mixture substantially free of chelating agent.

4. The process of claim 1, said mixture comprising antioxidant.

5. The process of claim 1, said mixture comprising chelating agent.

6. The process of claim 1, said mixture comprising gelatin.

7. The process of claim 1, further comprising removing the aqueous solvent to produce a dry dosage form.

8. The process of claim 7, wherein the dry dosage form is a powder.

9. The process of claim 7, wherein the dry dosage form is a tablet.

10. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 1.

11. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 2.

12. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 3.

13. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 4.

14. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 5.

15. A solid-state epinephrine pharmaceutical dosage form produced by the process of claim 6.

16. A solid-state epinephrine pharmaceutical dry dosage form produced by the process of claim 7.

17. A solid-state epinephrine pharmaceutical dry dosage form produced by the process of claim 8.

18. A solid-state epinephrine pharmaceutical dry dosage form produced by the process of claim 9.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0018] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with drawing(s) will be provided by the Office upon request and payment of the necessary fees.

[0019] FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D provide color photographs at t=0 and t=24 hours of the suspension of sample number /5 and tablets made from that suspension. FIG. 1A is the suspension at t=0. FIG. 1B is the suspension at t=24 hours. FIG. 1C is tablets at t=0. FIG. 1D is tablets at t=24 hours.

[0020] FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D provide color photographs at t=0 and t=24 hours of the suspension of sample/6 and tablets made from that suspension. FIG. 2A is the suspension at t=0. FIG. 2B is the suspension at t=24 hours. FIG. 2C is tablets at t=0. FIG. 2D is tablets at t=24 hours.

DETAILED DESCRIPTION

[0021] I provide experimental data for my various samples in the following Examples.

EXAMPLE 1

[0022] To test the effect of increased acidity on epinephrine stability, I had prepared epinephrine dissolved in aqueous solvent to make a solution containing 3.33% (w/w) epinephrine in solution, with the pH adjusted to pH 6 for some of my samples and pH 5 for my other samples. I number these samples /1A and /2A respectively. I had my samples assayed when made, and again after one month storage under normal storage conditions and in accelerated condition, and again after two months storage under normal and accelerated conditions. Results for normal storage conditions are show in Table 1.

TABLE-US-00001 TABLE 1 25 C./60% RH Results Epinephrine in Solution Months 0 1 2 Epinephrine Assay (% label claim) /1A 95.9 96.2 96.8 /2A 100.0 98.0 99.2 Sodium Metabisulfite (% label claim) /1A 50.4 42.0 45.0 /2A 19.7 13.3 15.4 Epinephrine sulfonate (% NPA) /1A 4.46 5.91 7.75 /2A 1.51 1.32 2.00 Limit 15 15 15 Total Unknown Impurities (% NPA) /1A 0.17 ND 0.14 /2A 0.12 0.54 0.18 Limit 1 1 1 Total Impurities (% NPA) /1A 4.63 5.91 7.89 /2A 1.63 1.86 2.18 Limit 16 16 16

[0023] The data for my samples show that after only one month of storage under normal conditions, my higher-pH sample shows measurably less epinephrine than my lower-pH sample. My higher pH sample continues to show inferior epinephrine content after two months storage. Similarly, my higher-pH sample shows markedly more residual sodium metabisulfite even on initial manufacture (t=0), indicating that it does not effectively complex oxygen free radicals at the higher pH. Similarly, my higher-pH sample shows markedly more epinephrine sulfonate (an undesirable impurity) and more total impurities (including unknown impurities) both on initial manufacture and subsequently. My data confirm the prior art teaching that epinephrine is more stable at lower pH.

[0024] Results for sample numbers /1A and /2A for accelerated storage conditions are shown in Table 2.

TABLE-US-00002 TABLE 2 40 C./75% RH Results Epinephrine in Solution Months 0 1 2 Epinephrine Assay (% label claim) /1A 95.9 86.2 86.2 /2A 100.0 94.0 93.9 Sodium Metabisulfite (% label claim) /1A 50.4 0.2 0.1 /2A 19.7 0.3 ND Epinephrine sulfonate (% NPA) /1A 4.46 19.53 19.60 /2A 1.51 6.27 7.35 Limit 15 15 15 Total Unknown Impurities (% NPA) /1A 0.17 0.40 0.79 /2A 0.12 0.68 0.58 Limit 1 1 1 Total Impurities (% NPA) /1A 4.63 19.94 20.39 /2A 1.63 6.95 7.93 Limit 16 16 16

[0025] The data for accelerated conditions show that my lower-pH sample retains >90% of its initial (labeled) amount of epinephrine for at least two months, yet after only one month my higher-pH sample falls below this and thus would be commercially unacceptable. Similarly, my lower-ph sample achieves below the acceptable limits of both epinephrine sulfonate and total impurities, while my higher-pH sample exceeds the acceptable limits for both, and does so quite rapidly, after only one month accelerated storage. These data again confirm the prior art teaching that epinephrine is more stable at lower pH.

[0026] Example 1 therefore confirms the prior art teaching that epinephrine is less stable at higher pH, i.e., raising the pH from 5 to 6 renders the solution so unstable as to be entirely unacceptable.

EXAMPLE 2

[0027] In Example 2, no acid/base is added, thus providing a mixture with a pH of about 7. In contrast to Example 1, which employed acidic pH and thus produced true solutions of epinephrine dissolved in solvent, Example 2 uses a neutral pH. The epinephrine thus does not dissolve. Rather, it remains in solid state, suspended (not dissolved) in the solvent system. Sample number /1 used 3.33% (w/w) epinephrine (as used in Example 1). Sample number /2 used 13.33% (w/w) epinephrine. I designate these samples as sample numbers /1 and /2, and provide the formulae for each in Table 3.

TABLE-US-00003 TABLE 3 Sample Number /1 /2 Material % w/w mg % w/w mg Purified water 87.32% 130.98 78.22% 117.33 Gelatin (EP/USP/JP) 4.80% 7.20 4.30% 6.45 (Fish HMW) Mannitol (EP/USP) 3.84% 5.76 3.44% 5.16 Sodium metabisulfite 0.30% 0.45 0.30% 0.45 (Ph Eur) Disodium EDTA (Ph Eur) 0.05% 0.08 0.05% 0.08 Epinephrine 3.33% 5.00 13.33% 20.00 Sucralose micronized NF 0.35% 0.53 0.35% 0.53 NaOH 0.00% 0.00 0.00% 0.00 Total 100.00% 150.00 100.00% 150.00

[0028] Sample numbers/1 and/2 were not acidic. To confirm that these samples produced solid state epinephrine rather than dissolved epinephrine, I had these samples assayed to determine whether the epinephrine had in fact dissolved into solution and if so, by what amount. I provide these data in Table 4.

TABLE-US-00004 TABLE 4 Epinephrine at Neutral pH Remains In Solid State Suspension Assay Testing % of Minimum Stoppage Epinephrine (Min 30) Theoretical Epinephrine Dissolved in Epinephrine Epinephrine % w/w Suspension Sample Content (n = 10) % w/w Dissolved Sample /1 Mean = 98.1% 3.33 0.42 12.5 LC Range: 92.9-101.9% LC % RSD = 3.2% /2 Mean = 102.0% 13.33 0.46 3.5 LC Range: 99.5-104.8% LC % RSD = 1.6%

[0029] These data show that without added acid, only about 0.45% of the total epinephrine dissolves in water at pH 7. The remainder remains in a solid state, suspended in the liquid.

[0030] As with my previous samples, I had sample numbers /1 and /2 tested for stability over one month, using both normal and accelerated storage conditions. On normal storage, sample /1 (3.33% w/w epinephrine) showed a markedly higher concentration (as a percentage of the total starting amount of epinephrine) of both epinephrine sulfonate and total impurities. The greater stability of sample number /2 appears due to the fact that it had far more moles of epinephrine at start. It thus was better able to withstand oxidation from the finite moles of oxygen in the formulation.

TABLE-US-00005 TABLE 5 25 C./60% RH Results for Solid-State Epinephrine (Sample Numbers/1 and/2) Months 0* 1 2 Epinephrine Assay (% label claim) /1 101.1 100.1 /2 102.5 101.8 Sodium Metabisulfite (% label claim) /1 68.2 58.4 /2 61.6 54.2 Epinephrine sulfonate (% NPA) /1 2.09 4.37 /2 0.44 1.15 Limit 15 15 15 Total Unknown Impurities (% NPA) /1 0.11 0.10 /2 NQ NQ Limit 1 1 1 Total Impurities (% NPA) /1 2.20 4.47 /2 0.44 1.15 Limit 16 16 16 *1 month at 5 C. used as a pseudo t = 0 time point

[0031] Accelerated stability results reiterate these results. After one month, the 3.33% sample (number /1) displayed so much epinephrine sulfonate and total impurities as to nearly exceed allowable limits.

TABLE-US-00006 TABLE 6 40 C./75% RH Results for Solid-State Epinephrine Months 0* 1 2 Epinephrine Assay (% label claim) /1 101.1 92.7 /2 102.5 101.0 Sodium Metabisulfite (% label claim) /1 68.2 20.9 /2 61.6 19.5 Epinephrine sulfonate (% NPA) /1 2.09 13.38 /2 0.44 2.99 Limit 15 15 15 Total Unknown Impurities (% NPA) /1 0.11 0.23 /2 NQ NQ Limit 1 1 1 Total Impurities (% NPA) /1 2.20 13.61 /2 0.44 2.99 Limit 16 16 16 *1 month at 5 C. used as a pseudo T = 0 time point

[0032] Example 2 thus shows that without added acid, only about 0.45% of the total epinephrine dissolves in water at pH 7, and the resulting solid-state epinephrine is vulnerable to oxidation within a short time.

EXAMPLE 3

[0033] In Example 3, I used the same general formula as in Example 2, but specified adding sodium hydroxide to increase the pH of the suspension to 8.5. As with Example 2, I compared 3.33% and 13.33% (w/w) epinephrine. I provide the formulae for Sample numbers/3 and/4 in Table 7.

TABLE-US-00007 TABLE 7 Sample Number /3 /4 Material % w/w mg % w/w mg Purified water 84.75% 127.13 75.71% 113.56 Gelatin (EP/USP/JP) 4.80% 7.20 4.30% 6.45 (Fish HMW) Mannitol (EP/USP) 3.84% 5.76 3.44% 5.16 Sodium metabisulfite 0.30% 0.45 0.30% 0.45 (Ph Eur) Disodium EDTA (Ph Eur) 0.05% 0.08 0.05% 0.08 Epinephrine 3.33% 5.00 13.33% 20.00 Sucralose micronized NF 0.35% 0.53 0.35% 0.53 NaOH 2.57% 3.85 2.51% 3.77 Total 100.00% 150.00 100.00% 150.00

[0034] Sample numbers /3 and /4 were basic pH. I thus had these samples assayed to determine whether the epinephrine dissolved into solution and if so, by what amount. I provide these data in Table 8.

TABLE-US-00008 TABLE 8 Epinephrine at pH 8.5 Remains In Solid State Suspension Assay Testing % of Minimum Stoppage Epinephrine (Min 30) Theoretical Epinephrine Dissolved in Epinephrine Epinephrine % w/w Suspension Sample Content (n = 10) % w/w Dissolved Sample /3 Mean = 99.9% 3.33 0.05 1.4 LC Range: 94.6-104.5% LC % RSD = 3.3% /4 Mean = 102.3% 13.33 0.23 1.7 LC Range: 101.7-105.4% LC % RSD = 1.4%

[0035] These data show that at a basic pH 8.5, only about 0.1% of the total epinephrine dissolves in watereven less than at pH 7. These data show that at pH 8.5, epinephrine remains in a solid state, suspended (not dissolved) in the liquid.

[0036] As with my previous samples, I had sample numbers /3 and /4 tested for stability over one month, using both normal and accelerated storage conditions. Surprisingly, both of my samples showed that on normal storage, both samples have a near or complete absence of both epinephrine sulfonate and of total impurities.

TABLE-US-00009 TABLE 9 25 C./60% RH Results Solid State Epinephrine (pH 8.5) Months 0* 1 2 Epinephrine Assay (% label claim) /3 101.2 101.5 /4 103.5 102.8 Sodium Metabisulfite (% label claim) /3 85.3 83.3 /4 84.3 82.6 Epinephrine sulfonate (% NPA) /3 NQ 0.19 /4 ND NQ Limit 15 15 15 Total Unknown Impurities (% NPA) /3 NQ NQ /4 ND ND Limit 1 1 1 Total Impurities (% NPA) /3 NQ 0.19 /4 ND NQ Limit 16 16 16 *1 month at 5 C. used as a pseudo T = 0 time point

[0037] Even more surprising, my samples continued to achieve such stability even on accelerated storage conditions.

TABLE-US-00010 TABLE 10 40 C./75% RH Results Solid-State Epinephrine At pH 8.5 Is Surprisingly Stable Months 0* 1 2 Epinephrine Assay (% label claim) /3 101.2 100.8 /4 103.5 102.8 Sodium Metabisulfite (% label claim) /3 85.3 79.6 /4 84.3 77.9 Epinephrine sulfonate (% NPA) /3 NQ 0.54 /4 ND 0.20 Limit 15 15 15 Total Unknown Impurities (% NPA) /3 NQ NQ /4 ND ND Limit 1 1 1 Total Impurities (% NPA) /3 NQ 0.54 /4 ND 0.20 Limit 16 16 16 *1 month at 5 C. used as a pseudo T = 0 time point

[0038] My samples of Example 3 show a remarkable stability. This stability is surprising in light of prior art teachings that high pH renders epinephrine unstable, and is surprising in light of my own experimental data (Examples 1 and 2) corroborating that. Table 11 provides a direct comparison of Sample numbers /1 to /4 (Examples 2 and 3).

TABLE-US-00011 TABLE 11 Solid-State Epinephrine at pH 7 and 8.5 Sodium Epinephrine Total Unknown Total Metabisulfite Epinephrine sulfonate Impuritiess Impurities Sample Time (% LC) (% LC) (%) (%) (%) /1 SH0* 68.2 101.1 2.09 0.11 2.20 SH24 51.1 98.0 1.93 0.12 2.05 /2 SH0* 61.6 102.5 0.44 NQ 0.44 SH24 32.3 99.2 0.46 0.10 0.56 /3 SH0* 85.3 101.2 NQ NQ NQ SH24 82.0 98.6 0.13 NQ 0.13 /4 SH0* 84.3 103.5 ND ND ND SH24 60.9 101.0 NQ ND NQ *1 month 5 C. stability data used

EXAMPLE 4

[0039] I wanted to determine whether the surprising stability achieved by my samples in Example 3 was due to the high pH or rather due to the sodium metabisulfate or disodium EDTA. In Example 4, I measured the effect of sodium metabisulfate and disodium EDTA on low-concentration (3.33% w/w epinephrine) solid-state suspensions. Example 4 thus used the same general formula as in sample number/1, but omitted sodium metabisulfate and disodium EDTA. Sample number /5 was pH 7. Sample number /6 was pH 8.5. I provide the formulae for Sample numbers /5 and /6 in Table 12.

TABLE-US-00012 TABLE 12 Sample Number /5 /6 Material % w/w mg % w/w mg Purified water 87.67% 131.51 87.83% 131.75 Gelatin (EP/USP/JP) 4.80% 7.20 4.80% 7.20 (Fish HMW) Mannitol (EP/USP) 3.84% 5.76 3.44% 5.16 Sodium metabisulfite 0.00% 0.00% (Ph Eur) Disodium EDTA (Ph Eur) 0.00% 0.00% Epinephrine 3.33% 5.00 3.33% 5.00 Sucralose micronized NF 0.35% 0.53 0.35% 0.53 NaOH 0.24% 0.36 Total 100.00% 150.00 100.00% 150.00

[0040] As with my previous samples, I had sample numbers /5 and /6 tested for stability over one month, using both normal and accelerated storage conditions. Surprisingly, both of my samples showed that on normal storage, even without added sodium metabisulfate and disodium EDTA, both samples have a near or complete absence of both epinephrine sulfonate and of total impurities.

TABLE-US-00013 TABLE 13 25 C./60% RH Results Solid-State Epinephrine Needs No Anti-Oxidant Nor Chelating Agent Months 0* 1 2 Epinephrine Assay (% label claim) /5 101.2 101.5 /6 102.1 101.7 Epinephrine sulfonate (% NPA) /5 ND ND /6 ND ND Limit 15 15 15 Total Unknown Impurities (% NPA) /5 ND ND /6 ND ND Limit 1 1 1 Total Impurities (% NPA) /5 ND ND /6 ND ND Limit 16 16 16 *1 month at 5 C. used as a pseudo T = 0 time point

[0041] Even more surprising, my samples continued to achieve such stability even on accelerated storage conditions.

TABLE-US-00014 TABLE 14 40 C./75% RH Results Solid-State Epinephrine Needs No Anti-Oxidant Nor Chelating Agent Months 0* 1 2 Epinephrine Assay (% label claim) /5 101.2 102.1 /6 102.1 102.4 Epinephrine sulfonate (% NPA) /5 ND ND /6 ND ND Limit 15 15 15 Total Unknown Impurities (% NPA) /5 ND NQ /6 ND ND Limit 1 1 1 Total Impurities (% NPA) /5 ND NQ /6 ND ND Limit 16 16 16 *1 month at 5 C. used as a pseudo T = 0 time point

[0042] My samples of Example 4 show a remarkable stability, even though these samples have no added anti-oxidant. This stability is surprising in light of prior art teachings that anti-oxidant is necessary even with the low-pH solutions conventional in the art. This stability is particularly surprising in light of the prior art teaching that high pH renders epinephrine unstable, and in light of my own experimental data (Examples 1 and 2) corroborating that.

EXAMPLE 5

[0043] To determine whether my solid-phase epinephrine suspensions might be able to make solid dosage forms, I had tablets made using the suspension of sample numbers /5 and /6. The solid dosage was made by loading the liquid suspension into an aluminum blister-pack form, freezing under liquid nitrogen and drying to remove water. The resulting lyophilized solid dosage is highly porous, and thus disperses almost instantly in the mouth.

[0044] FIG. 1 shows color photographs of the suspension of sample number /5, and tablets made from that suspension, at t=0 and t=24 hours. FIG. 2 shows color photographs of the suspension of sample number /6, and tablets made from that suspension, at t=0 and t=24 hours. These photographs confirm that my solid-phase suspensions can be used to make solid dosage forms. These formulae lack anti-oxidant and lack chelating agent. They thus acquire a pink hue (likely due to the formation of adrenochrome). They nonetheless display very little epinephrine sulfonate and very little total impurities.

SUMMARY

[0045] Given my disclosure, the artisan can readily make other stable solid formulations of solid-state epinephrine. For example, while many of my samples are at pH 8.5, a higher or a somewhat lower pH would also be suitable, as long as the epinephrine remains in solid state and as long as it retains the surprising resistance to oxidation my samples exemplify. Similarly, while Example 5 uses suspension to make tablets, the artisan can pulverize the resulting freeze dried mass to make an inhalable dry powder equivalent to art-known inhalable liquid epinephrine solutions (e.g., PRIMATENE MIST brand epinephrine nasal solution). Similarly, while my Examples produce tablets, one could use solid-state epinephrine in a basic pH solvent system as a liquid dosage form. Similarly, the excipients used in my Examples are not essential for many dosage forms. For example, gelatin is useful to preserve structural integrity of a tablet, but is not needed for a powder. Sucralose is useful as a sweetener for oral dosage forms, but is unnecessary for e.g., inhaled powders. I thus intend the legal coverage of my patent to be defined not by my specific Examples, but by my legal claims and permissible equivalents thereto.