Beclomethasone and Betamethasone

Beclomethasone and betamethasone are two very closely related glucocorticoid immunosuppressants with identical structures, except in betamethasone, the heteroatom substituent on the steroidal backbone is fluorine (12), while in beclomethasone, the heteroatom substituent is chlorine (13). The chemical structures of beclomethasone and betamethasone dipropionate are depicted in Figure 1. Frequently, these two drugs are administered as salt forms (dipropionate, sodium phosphate) due to their low aqueous solubility in their native forms. Typically, betamethasone is administered parenterally, topically, or via the ophthalmic route, while beclomethasone is administered topically or inhaled.

Beclovent® Aerosol for Inhalation (Glaxo Smithkline, Research Triangle Park, NC) is a commercial formulation of beclomethasone dipropionate indicated for asthma and other pulmonary autoimmune conditions (14). Beclomethasone dipropionate is sparingly water soluble and poorly mobilized from the injection site for subcutaneous or intramuscular administration, so pulmonary formulation of this drug is more efficacious than the parenteral formulation. This formulation is composed of micro-crystalline beclomethasone dipropionate with oleic acid excipients added as a surfactant (14). Beclovent Aerosol is formulated in a pressurized metered dose inhaler (pMDI) device with chlorofluorocarbons (CFCs) such as trichloromonofluoromethane and dichlorodifluoromethane used as propel-lant agents. The propellants offer an additional advantage, forming a clathrate with beclomethasone dipropionate, trapping the drug molecule around a "cage" of propellant molecules through dispersion interactions. After actuation of the pMDI, most of the drug is deposited in the mouth and throat areas, while only a fraction is deposited in the deep lung tissue. A considerable amount of the formulation is swallowed, indicating that the particle size of the drug after actuation is larger than the respirable fraction

Table 1 Selected Immunosuppressant Drugs' Physicochemical Properties

Drug

BCS classification

Aqueous solubility3

log P app

PGP interaction

CYP 3A4 interaction

Prednisolone

Hydrocortisone

Dexamethasone

Cyclosporin

Tacrolimus

Sirolimus

Azithioprine

Methotrexate

1 (for salt form)

1 (for sodium salt) 1 (for sodium salt)

481.1 mg/L (9] 896.6 mg/L (9) 254.8 mg/L (9) 0.028 mg/mL (36) 0.012mg/mL (42) 0.026 mg/mL (53) 272 mg/L (56) 2600 mg/L (56)

-1.08 (56)

PGP substrate (9) PGP substrate (9) PGP substrate (9) PGP substrate (35) PGP substrate (35) PGP substrate (35) none known none known

CYP3A4 substrate (9) CYP3A4 substrate (9) CYP3A4 substrate (9) CYP3A4 substrate (35) CYP3A4 substrate (35) CYP3A4 substrate (35) none known none known

Note\ BCS classification is based on aqueous solubility. PGP interaction and CYP 3A4 interaction is qualitative. Log P values are calculated. a Solubility is given as the value in water at 25°C.

Note\ BCS classification is based on aqueous solubility. PGP interaction and CYP 3A4 interaction is qualitative. Log P values are calculated. a Solubility is given as the value in water at 25°C.

CH2OCOC2H5

(A) Beclomethasone

(A) Beclomethasone

ch2-oh

(C) Budesonide

(C) Budesonide

Beclomethasone Betamethasone

(E) Cyclosporin A

Beclomethasone Betamethasone

(B) Betamethasone Dipropionate

(B) Betamethasone Dipropionate

OH Chiral

O OH

Beclomethasone Betamethasone
(D) Dexamethasone

(E) Cyclosporin A

Beclomethasone Betamethasone

Figure 1 See caption on page 415.

(G) Sirolimus

Figure 1 See caption on page 415.

Beclomethasone Betamethasone

(H) Everolimus

(H) Everolimus

What Drugs Interact With Azathioprine

(I) Azathioprine n N (J) Methotrexate

Figure 1 The chemical structures of immunosuppressant drugs detailed in this article. (A) Beclomethasone, (B) Betamethasone Dipropionate, (C) Budesonide, (D) Dexamethasone, (E) Cyclosporin A, (F) Tacrolimus, (G) Sirolimus, (H) Enverolimus, (I) Azathioprine, (J) Methotrexate.

(I) Azathioprine n N (J) Methotrexate

Figure 1 The chemical structures of immunosuppressant drugs detailed in this article. (A) Beclomethasone, (B) Betamethasone Dipropionate, (C) Budesonide, (D) Dexamethasone, (E) Cyclosporin A, (F) Tacrolimus, (G) Sirolimus, (H) Enverolimus, (I) Azathioprine, (J) Methotrexate.

(3-5 ^m) needed for lung deposition. Additionally, the Beclovent Aerosol for Inhalation contains ozone-depleting chlorofluorocarbons which are being phased out of production (14).

Other pMDI formulations of beclomethasone have been reported which do not contain ozone-depleting chlorofluorocarbons. Rocca-Serra et al. have studied the efficacy and tolerability of beclomethasone pMDI formulations which contain hydrofluroalkane (HFA-134a) propellants as an alternative to CFCs (15). These propellants do not show a propensity to form clathrates with the drug, but they do effectively propel the drug into the patients' respiratory system in the desired respirable fraction. This study involved monitoring asthmatic patients' in two treatment groups: one group using the commercial Beclojet® with CFC containing propellants and the other using the beclomethasone/HFA-containing propellant. The study did not involve a placebo group because of ethical concerns about harm to human asthmatic subjects not receiving treatment for their conditions. A double-blind study was designed with randomized groups receiving one of the two treatments over a 6-week study period. Blood cortisol concentrations, adverse events, and treatment efficacy were studied. Peak expiratory flow (PEF), the measure of breathing efficiency, was the main measure of efficacy of the formulations. PEF was measured both in the morning and in the evening following treatment with the two different beclomethasone pMDI's. In the protocol study group, the average starting baseline PEF for patients was measured at 392.6 L/min for the HFA group and 407.3 L/min for the CFC group. Final PEF measurements showed 403.9 L/min in the HFA group and 414.7 L/min in the CFC group. The protocol study's baseline to final PEF ratios were similar, showing a ratio of 1.06 for the HFA group and 1.05 for the CFC group. The results of the study also showed that the particle sizes of aerosols produced by the

HFA formulation were smaller than those produced by the CFC formulation, resulting in the need to half the dose when switching from the CFC to the HFA formulation. The present study demonstrated that beclomethasone HFA was not statistically inferior to the beclomethasone CFC formulation for adjusting morning PEF, evening PEF, or PEF variability. The study constituted 449 patients, with a total number of adverse events involving the respiratory system being 57 in the HFA group, compared with 35 in the CFC group, most of the adverse events being mild to moderate. The study concluded that non-extra fine beclomethasone HFA-134a formulation was equivalent to the CFC formulation used in the study with regard to clinical efficacy and tolerability in patients with mild to severe asthma (15).

Another study involving the use of HFA propellant over CFC propellant in pMDI formulations of beclomethasone was conducted, evaluating the quality of life of asthmatic patients using these treatments. Juniper et al. reported data using clinical indexes of patients switched from conventional beclomethasone treatment to approximately half the dose of extra fine beclomethasone aerosol (16). This study involved human asthmatic volunteers with a total number of 152 male patients and 40 female patients. The formulation of the HFA-BDP pMDI was altered in one group to produce extra fine aerosols with an average particle size of 1.1 |m. The baseline (pre-treatment) quality of life scores were measured by a 7-point value score with instance of severe asthma symptoms occurring (1 = severe asthma all the time to 7 = severe asthma none of the time). The average baseline score for male patients was 5.45, while the average baseline score for female patients was 5.36. Patients were randomized in a 3:1 HFA-BDP group (400-1600 |ig/day), a 3:1 CFC-BDP group (400-1600 |ig/day), and an HFA-BDP group with approximately half the dose of BDP administered (200-800 |g/day). The duration of the study was 12 months, and the mean change from baseline was analyzed. Results showed that the overall change in baseline quality of life was increased to about 0.18 with the HFA (200-800 |g/day) group at 2 months, while the CFC group (400-1600 mg/day) increased only 0.8 over the 2 month time period. At 4 months, the HFA group (200-800 |g/day) showed increased quality of life scores of about 2.4 and the CFC group (400-1600 |g/day) increased to 1.6, while at 8 months, the HFA group (200-800 |g/day) increased to 2.8, with the CFC group (400-1600 |g/day) decreasing to 0.7. At the final time point of 12 months, the HFA (200-800 |g/day) the scores had increased to 0.32 from baseline, while the HFA (400-1600 |g/day) remained constant at about 0.33. The study concluded that patients switched from CFC-BDP to approximately half the dose of HFA-BDP extra fine aerosol experienced significant improvement in asthma-specific quality of life. The reason for the discrepancy between quality of life and clinical outcomes was that HFA-BDP spray was deposited in more in the peripheral airways as well as alveolar sacs. Also, improvement in quality of life seen in the present study developed progressively over the 12 month time period, suggesting that improvement could be increased with even longer term use of HFA-BDP (200-800 mg/day). The difference in quality of life score was significant between the HFA-BDP group (200-800 mg/day) versus the CFC (800-1600 mg/day) group by 0.24 standard deviations. The study concludes that switching from CFC based BDP aerosols to extra fine aerosol mist with HFA-BDP (200-8000 mg/day) may experience clinically important improvements in quality of life. This study also confirmed from shorter studies that asthma control can be maintained with approximately half the dose of HFA-BDP versus CFC based BDP treatment (16).

NanoSystems® particle size reduction technology has been used to produce drug formulations of immunosuppressants with improved physicochemical properties (17). The Nanocrystal process was initially developed by NanoSystems, a division of Elan Pharmaceutical Company. This process involves the use of media milling technology to formulate poorly water soluble drugs into nanocrystalline particles which offer improved drug delivery (17). In this process, large micron sized crystalline particles of poorly water soluble compounds are milled in aqueous solution containing water-soluble stabilizer solutions. This process produces physically stable dispersions consisting of nanometer sized drug crystals that do not spontaneously reaggregate due to the surface adsorption of stabilizing excipients. High energy wet milling of the crystals in the presence of the stabilizing excipients causes the drug crystals to fracture to nano-sized particles. Polymeric excipients then adsorb to the crystal surface of the particles, inhibiting aggregation and particle growth of the crystals and providing stable dispersions of the drug crystals. Following milling for 30-60 min, unimodal distribution profiles and mean particle diameters of <200 nm have been reported. This type of processing is especially useful in formulating drugs that are poorly water soluble and do not dissolve readily in the stabilizer-containing aqueous media in which they are milled (17). A schematic of the Nanocrystal technology is shown in Fig. 2 (17). A comparison of the size of beclomethasone dipropionate crystals both before and after Nanocrystal processing is shown in Fig. 3 (4).

The use of Nanocrystal technology for enhancing delivery of beclomethasone dipropionate (BCD) is an example of novel formulation design of immunosuppressant drugs. An initial study involved the preparation of pulmonary BCD using polyvinyl alcohol (PVA) as a stabilizer. Unmilled BCD showed a mean particle size of 10.5 mm, and after Nanocrystal processing of BCD in 2.5% PVA, the mean particle size was reduced to 267 ± 84 nm (18). The particle size of the crystals remained constant throughout the study, and following 7 months of storage at room temperature, the mean size was found to increase only slightly to 282 ± 73 nm (18). A second study was conducted, using BCD wet-milled

Wet Bead Milling Minicer

Figure 2 The media milling process is shown in a schematic representation. The milling chamber charged with polymeric media is the active component of the mill. The mill can be operated in a batch or recirculation mode. A crude slurry consisting of drug, water, and stabilizer is fed into the milling chamber and processed into a nanocrystal dispersion. The typical residence time required to generate a nanometer-sized dispersion with a mean diameter of <200 nm is 30-60 min. Source: From Ref. 17.

Figure 2 The media milling process is shown in a schematic representation. The milling chamber charged with polymeric media is the active component of the mill. The mill can be operated in a batch or recirculation mode. A crude slurry consisting of drug, water, and stabilizer is fed into the milling chamber and processed into a nanocrystal dispersion. The typical residence time required to generate a nanometer-sized dispersion with a mean diameter of <200 nm is 30-60 min. Source: From Ref. 17.

with Tyloxapol 2% w/w solution in water (4). Following production of the BCD aqueous dispersion, the formulation was nebulized using an Omron Micro-air® NEU-30 nebulizer. The droplet size of the nebulized dispersion was controlled within a range of 1-7 ^m, and the nebulized dispersion was analyzed using Andersen cascade impaction (4). When viewed as a percentage of emitted dose through the mouthpiece, the respirable fraction ranged from 56 to 72% for the nanocrystalline formulation versus 36% for the propellant system. In addition, the throat deposition was 9-10% of the emitted dose for the novel dispersion, as compared to 53% for the commercial product. Therefore, the novel dispersion technology provides greater deposition of drug to the conducting airways and deep lung tissue both in quantity and as a percent of emitted dose than the commercial BCD product, lowering the dose needed for therapy and decreasing potential side effects. Also, the use of nebulized aqueous dispersions of nanocrystalline BCD represents an environmentally sound alternative to the use of chlorofluorocarbon based propellant formulations (4).

Sem Beclomethasone
Figure 3 SEM of (A) micronized bulk beclomethasone dipropionate; and (B) beclomethasone dipropionate media milled using the Nanosystems® process. Source: From Ref. 4.

Dry powder pulmonary formulations of BCD within mucoadhesive microspheres were studied in order to increase the residence time in the lungs and decrease dosing frequency and overall dose (19). The micro-spheres were spray-dried from either an aqueous suspension or ethanolic solution containing BCD and the mucoadhesive polymer hydroxypropyl cellulose (HPC). Formulations produced by aqueous suspension showed crystalline characteristics, while those produced from ethanolic solution showed amorphous character. Amorphous beclomethasone dipropionate and hydroxypropylcellulose (aBCD/HPC) microspheres showed rapid absorption of the drug. Crystalline beclomethasone dipropionate and hydroxypropylcellulose (cBDC/HPC) microspheres showed increased residence time, being retained in the lung longer (with 86% remaining after 180 min), and showed sustained drug release. Bulk crystalline BCD (cBCD) administered without formulation into HPC microspheres and aBCD/HPC showed less than 17% dose remaining and less than 5% dose remaining, respectively, after 180 min. The aBCD/HPC formulation, with a higher apparent solubility and dissolution rate, was able to be absorbed faster than the crystalline forms of the drug, despite being formulated with a mucoadhesive carrier. Both of the HPC microsphere formulations (cBCD/ HPC and aBCD/HPC) showed better efficacy against eosinophil accumulation than did the bulk drug substance cBCD. Inhaled cBCD/HPC microspheres showed a 50-60% decrease in the accumulation of lung eosinophils at the 6 and 24 h time points after dosing compared to the aerosolized bulk drug substance (19), even with overall dosing of the BCD reduced from 480 |g of the bulk BCD to 88 |g of the cBCD/HPC formulation. It was shown that five times the dosing of BCD bulk was only effective from 1 to 6 h compared to 24-h efficacy with the cBCD/HPC formulations. Therefore, by controlling the release and retention of BCD in the airways, mucoadhesive BCD microspheres are able to prolong the pharmacokinetic/pharmacodynamic profiles of this drug without increasing drug dose, and, hence unwanted side-effects (19).

Betamethasone sodium phosphate (BSP) encapsulated into poly(lactic/ glycolic acid) (PLGA) nanoparticles was evaluated for its effectiveness in the treatment of experimentally induced arthritis. Higaki et al. used the biodegradable nanoparticle/steroid formulation for adjuvant induced arthritis (AA) and antibody induced arthritis (AbIA) (7). The PLGA/BSP nanoparticles were administered intravenous (IV), while the bulk BSP was administered subcutaneously at the site of induced arthritis. The inflammation rate in the test subject animals was evaluated against two control groups treated only with blank PLGA nanoparticles and saline. In the AA mice, at 1 day post treatment, the PLGA/BSP nanoparticles showed 64% inflammation rate, while the bulk BSP administered at 100 | g and 300 | g showed inflammation rates of 68% and 78%, respectively. All three treatment groups showed decreased inflammation rates compared with the control groups which still showed 100% inflammation. In the AA mice, at 7 days post treatment, the PLGA/BSP nanoparticles inflammation rate was 76% vs. 84% and 87% for the bulk BSP groups (100 |g and 300 |g dosing), while the control groups still had 100% inflammation rates. A 36-24% decrease in inflammation was obtained after 1 day and maintained for 1 week with a single injection of 100 | g of PLGA-nanosteroid. The PLGA-nanosteroid particles were also effective against AbIA in mice. The inflammation in the joints of mice induced with AbIA was scored for inflammation on a scale of 0-5 (0 = no inflammation; 5 = maximum inflammation). Twelve days after treatment, the arthritis score for the vehicle alone (PLGA) was 3.9, while the arthritis score for the PLGA/BSP was 1.3 and the BSP 100 ^g dose was 2.4. The authors state that the PLGA nanoparticles may protect BSP against conversion and degradation in circulation, preventing the rapid and extensive tissue distribution that occurs with free BSP. The results of this study indicate that a single IV dose of hydrophilic BSP encapsulated in PLGA nanoparticles can lead to rapid, complete, and durable resolution of arthritis inflammation, owing to the enhanced preferential localization of the BSP in the synovial tissue. The observed strong therapeutic benefit obtained with PLGA-nanosteroid is due to the sustained release of the BSP over the longer time period as compared to injection of the bulk BSP. Therefore, targeted drug delivery of BSP using a sustained release PLGA nanosteroid delivery system shows successful treatment against experimental arthritis.

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Responses

  • Grimalda Twofoot
    Can beclomethasone used in place of betamethosone?
    1 year ago
  • vittorio
    Is betamethazone related to beclomethasone?
    11 months ago
  • elena
    Which is stronger beclomethasone or betamethasone?
    7 months ago
  • Vince Tanguay
    Can you have both betamethasone cream and beclometasone inhaler?
    5 months ago
  • CHRISTINE
    Is Beclomethason an immunosuppressant?
    2 months ago
  • fiyori
    Is Betamethasone & Beclometasone Topical same?
    29 days ago

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